Cytosolic sensors of pathogen-associated DNA (Homo sapiens)
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Description
Presence of pathogen-associated DNA in cytosol induces type I IFN production. Several intracellular receptors have been implicated to some degree. These include DNA-dependent activator of interferon (IFN)-regulatory factors (DAI) (also called Z-DNA-binding protein 1, ZBP1), absent in melanoma 2 (AIM2), RNA polymerase III (Pol III), IFN-inducible protein IFI16, leucine-rich repeat flightless interacting protein-1 (LRRFIP1), DEAH-box helicases (DHX9 and DHX36), DEAD-box helicase DDX41, meiotic recombination 11 homolog A (MRE11), DNA-dependent protein kinase (DNA-PK), cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING).
Detection of cytosolic DNA requires multiple and possibly redundant sensors leading to activation of the transcription factor NF-kappaB and TBK1-mediated phosphorylation of the transcription factor IRF3. Cytosolic DNA also activates caspase-1-dependent maturation of the pro-inflammatory cytokines interleukin IL-1beta and IL-18. This pathway is mediated by AIM2.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1834949</div>
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- Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS, Fitzgerald KA, Paludan SR, Bowie AG.; ''IFI16 is an innate immune sensor for intracellular DNA.''; PubMed Europe PMC Scholia
- Jønsson KL, Laustsen A, Krapp C, Skipper KA, Thavachelvam K, Hotter D, Egedal JH, Kjolby M, Mohammadi P, Prabakaran T, Sørensen LK, Sun C, Jensen SB, Holm CK, Lebbink RJ, Johannsen M, Nyegaard M, Nyegaard M, Mikkelsen JG, Kirchhoff F, Paludan SR, Jakobsen MR.; ''IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP.''; PubMed Europe PMC Scholia
- Ouyang S, Song X, Wang Y, Ru H, Shaw N, Jiang Y, Niu F, Zhu Y, Qiu W, Parvatiyar K, Li Y, Zhang R, Cheng G, Liu ZJ.; ''Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding.''; PubMed Europe PMC Scholia
- Nguyen JB, Modis Y.; ''Crystal structure of the dimeric coiled-coil domain of the cytosolic nucleic acid sensor LRRFIP1.''; PubMed Europe PMC Scholia
- Kondo T, Kobayashi J, Saitoh T, Maruyama K, Ishii KJ, Barber GN, Komatsu K, Akira S, Kawai T.; ''DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking.''; PubMed Europe PMC Scholia
- Gao D, Wu J, Wu YT, Du F, Aroh C, Yan N, Sun L, Chen ZJ.; ''Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses.''; PubMed Europe PMC Scholia
- Yang P, An H, Liu X, Wen M, Zheng Y, Rui Y, Cao X.; ''The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway.''; PubMed Europe PMC Scholia
- Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J.; ''RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.''; PubMed Europe PMC Scholia
- Jin L, Lenz LL, Cambier JC.; ''Cellular reactive oxygen species inhibit MPYS induction of IFNβ.''; PubMed Europe PMC Scholia
- Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, Kawai T, Hoshino K, Takeda K, Akira S.; ''The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection.''; PubMed Europe PMC Scholia
- Yin Q, Tian Y, Kabaleeswaran V, Jiang X, Tu D, Eck MJ, Chen ZJ, Wu H.; ''Cyclic di-GMP sensing via the innate immune signaling protein STING.''; PubMed Europe PMC Scholia
- Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P, Shu HB.; ''The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.''; PubMed Europe PMC Scholia
- Koike M, Kose S, Furuta M, Taniguchi N, Yokoya F, Yoneda Y, Imamoto N.; ''beta-Catenin shows an overlapping sequence requirement but distinct molecular interactions for its bidirectional passage through nuclear pores.''; PubMed Europe PMC Scholia
- Sharma M, Jamieson C, Johnson M, Molloy MP, Henderson BR.; ''Specific armadillo repeat sequences facilitate β-catenin nuclear transport in live cells via direct binding to nucleoporins Nup62, Nup153, and RanBP2/Nup358.''; PubMed Europe PMC Scholia
- Jin L, Hill KK, Filak H, Mogan J, Knowles H, Zhang B, Perraud AL, Cambier JC, Lenz LL.; ''MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP.''; PubMed Europe PMC Scholia
- Chen H, Sun H, You F, Sun W, Zhou X, Chen L, Yang J, Wang Y, Tang H, Guan Y, Xia W, Gu J, Ishikawa H, Gutman D, Barber G, Qin Z, Jiang Z.; ''Activation of STAT6 by STING is critical for antiviral innate immunity.''; PubMed Europe PMC Scholia
- Dragan AI, Hargreaves VV, Makeyeva EN, Privalov PL.; ''Mechanisms of activation of interferon regulator factor 3: the role of C-terminal domain phosphorylation in IRF-3 dimerization and DNA binding.''; PubMed Europe PMC Scholia
- Yoneyama M, Fujita T.; ''RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity.''; PubMed Europe PMC Scholia
- Solt LA, Madge LA, May MJ.; ''NEMO-binding domains of both IKKalpha and IKKbeta regulate IkappaB kinase complex assembly and classical NF-kappaB activation.''; PubMed Europe PMC Scholia
- Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ.; ''The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells.''; PubMed Europe PMC Scholia
- Goubau D, Deddouche S, Reis e Sousa C.; ''Cytosolic sensing of viruses.''; PubMed Europe PMC Scholia
- Li Y, Wu Y, Zheng X, Cong J, Liu Y, Li J, Sun R, Tian ZG, Wei HM.; ''Cytoplasm-Translocated Ku70/80 Complex Sensing of HBV DNA Induces Hepatitis-Associated Chemokine Secretion.''; PubMed Europe PMC Scholia
- Jacobs MD, Harrison SC.; ''Structure of an IkappaBalpha/NF-kappaB complex.''; PubMed Europe PMC Scholia
- Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y, Iyer SS, Zaver SA, Schenk M, Zeng S, Zhong W, Liu ZJ, Modlin RL, Liu YJ, Cheng G.; ''The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response.''; PubMed Europe PMC Scholia
- Ishikawa H, Ma Z, Barber GN.; ''STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.''; PubMed Europe PMC Scholia
- Bose SK, Meyer K, Di Bisceglie AM, Ray RB, Ray R.; ''Hepatitis C virus induces epithelial-mesenchymal transition in primary human hepatocytes.''; PubMed Europe PMC Scholia
- Hasan M, Koch J, Rakheja D, Pattnaik AK, Brugarolas J, Dozmorov I, Levine B, Wakeland EK, Lee-Kirsch MA, Yan N.; ''Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes.''; PubMed Europe PMC Scholia
- DeFilippis VR, Alvarado D, Sali T, Rothenburg S, Früh K.; ''Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1.''; PubMed Europe PMC Scholia
- Sato M, Tanaka N, Hata N, Oda E, Taniguchi T.; ''Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene.''; PubMed Europe PMC Scholia
- Espinosa A, Hennig J, Ambrosi A, Anandapadmanaban M, Abelius MS, Sheng Y, Nyberg F, Arrowsmith CH, Sunnerhagen M, Wahren-Herlenius M.; ''Anti-Ro52 autoantibodies from patients with Sjögren's syndrome inhibit the Ro52 E3 ligase activity by blocking the E3/E2 interface.''; PubMed Europe PMC Scholia
- Bailey SL, Harvey S, Perrino FW, Hollis T.; ''Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune disease.''; PubMed Europe PMC Scholia
- Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, Serganov AA, Liu Y, Jones RA, Hartmann G, Tuschl T, Patel DJ.; ''Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase.''; PubMed Europe PMC Scholia
- Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T.; ''Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300.''; PubMed Europe PMC Scholia
- Jin L, Waterman PM, Jonscher KR, Short CM, Reisdorph NA, Cambier JC.; ''MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals.''; PubMed Europe PMC Scholia
- Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC Scholia
- Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, Akira S, Gill MA, García-Sastre A, Katze MG, Gale M.; ''Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.''; PubMed Europe PMC Scholia
- Yoneyama M, Fujita T.; ''Function of RIG-I-like receptors in antiviral innate immunity.''; PubMed Europe PMC Scholia
- Qin BY, Liu C, Srinath H, Lam SS, Correia JJ, Derynck R, Lin K.; ''Crystal structure of IRF-3 in complex with CBP.''; PubMed Europe PMC Scholia
- Marié I, Smith E, Prakash A, Levy DE.; ''Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain.''; PubMed Europe PMC Scholia
- Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE.; ''STING is a direct innate immune sensor of cyclic di-GMP.''; PubMed Europe PMC Scholia
- Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U.; ''Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases.''; PubMed Europe PMC Scholia
- Peters NE, Ferguson BJ, Mazzon M, Fahy AS, Krysztofinska E, Arribas-Bosacoma R, Pearl LH, Ren H, Smith GL.; ''A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus.''; PubMed Europe PMC Scholia
- Zhang X, Brann TW, Zhou M, Yang J, Oguariri RM, Lidie KB, Imamichi H, Huang DW, Lempicki RA, Baseler MW, Veenstra TD, Young HA, Lane HC, Imamichi T.; ''Cutting edge: Ku70 is a novel cytosolic DNA sensor that induces type III rather than type I IFN.''; PubMed Europe PMC Scholia
- Takahasi K, Suzuki NN, Horiuchi M, Mori M, Suhara W, Okabe Y, Fukuhara Y, Terasawa H, Akira S, Fujita T, Inagaki F.; ''X-ray crystal structure of IRF-3 and its functional implications.''; PubMed Europe PMC Scholia
- Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, Lu Y, Miyagishi M, Kodama T, Honda K, Ohba Y, Taniguchi T.; ''DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response.''; PubMed Europe PMC Scholia
- Kim T, Pazhoor S, Bao M, Zhang Z, Hanabuchi S, Facchinetti V, Bover L, Plumas J, Chaperot L, Qin J, Liu YJ.; ''Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells.''; PubMed Europe PMC Scholia
- Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA.; ''Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.''; PubMed Europe PMC Scholia
- Yoneyama M, Fujita T.; ''Structural mechanism of RNA recognition by the RIG-I-like receptors.''; PubMed Europe PMC Scholia
- Triantafilou K, Eryilmazlar D, Triantafilou M.; ''Herpes simplex virus 2-induced activation in vaginal cells involves Toll-like receptors 2 and 9 and DNA sensors DAI and IFI16.''; PubMed Europe PMC Scholia
- Chiu YH, Macmillan JB, Chen ZJ.; ''RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.''; PubMed Europe PMC Scholia
- Chen W, Royer WE.; ''Structural insights into interferon regulatory factor activation.''; PubMed Europe PMC Scholia
- Kaiser WJ, Offermann MK.; ''Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif.''; PubMed Europe PMC Scholia
- Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J.; ''DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB.''; PubMed Europe PMC Scholia
- Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed Europe PMC Scholia
- Chen ZJ.; ''Ubiquitin signalling in the NF-kappaB pathway.''; PubMed Europe PMC Scholia
- Cui J, Li Y, Zhu L, Liu D, Songyang Z, Wang HY, Wang RF.; ''NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4.''; PubMed Europe PMC Scholia
- Wu J, Sun L, Chen X, Du F, Shi H, Chen C, Chen ZJ.; ''Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA.''; PubMed Europe PMC Scholia
- Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng G.; ''Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.''; PubMed Europe PMC Scholia
- Hansen K, Prabakaran T, Laustsen A, Jørgensen SE, Rahbæk SH, Jensen SB, Nielsen R, Leber JH, Decker T, Horan KA, Jakobsen MR, Paludan SR.; ''Listeria monocytogenes induces IFNβ expression through an IFI16-, cGAS- and STING-dependent pathway.''; PubMed Europe PMC Scholia
- Ryjenkov DA, Simm R, Römling U, Gomelsky M.; ''The PilZ domain is a receptor for the second messenger c-di-GMP: the PilZ domain protein YcgR controls motility in enterobacteria.''; PubMed Europe PMC Scholia
- Horan KA, Hansen K, Jakobsen MR, Holm CK, Søby S, Unterholzner L, Thompson M, West JA, Iversen MB, Rasmussen SB, Ellermann-Eriksen S, Kurt-Jones E, Landolfo S, Damania B, Melchjorsen J, Bowie AG, Fitzgerald KA, Paludan SR.; ''Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors.''; PubMed Europe PMC Scholia
- Kishore N, Huynh QK, Mathialagan S, Hall T, Rouw S, Creely D, Lange G, Caroll J, Reitz B, Donnelly A, Boddupalli H, Combs RG, Kretzmer K, Tripp CS.; ''IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2.''; PubMed Europe PMC Scholia
- Panne D, McWhirter SM, Maniatis T, Harrison SC.; ''Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch.''; PubMed Europe PMC Scholia
- Huang J, Liu T, Xu LG, Chen D, Zhai Z, Shu HB.; ''SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways.''; PubMed Europe PMC Scholia
- DeFilippis VR, Sali T, Alvarado D, White L, Bresnahan W, Früh KJ.; ''Activation of the interferon response by human cytomegalovirus occurs via cytoplasmic double-stranded DNA but not glycoprotein B.''; PubMed Europe PMC Scholia
- Dey B, Dey RJ, Cheung LS, Pokkali S, Guo H, Lee JH, Bishai WR.; ''A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis.''; PubMed Europe PMC Scholia
- Shu C, Yi G, Watts T, Kao CC, Li P.; ''Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system.''; PubMed Europe PMC Scholia
- Honda K, Yanai H, Takaoka A, Taniguchi T.; ''Regulation of the type I IFN induction: a current view.''; PubMed Europe PMC Scholia
- Zhang J, Hu MM, Wang YY, Shu HB.; ''TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination.''; PubMed Europe PMC Scholia
- Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
- Yazdi S, Naumann M, Stein M.; ''Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB.''; PubMed Europe PMC Scholia
- Kim K, Khayrutdinov BI, Lee CK, Cheong HK, Kang SW, Park H, Lee S, Kim YG, Jee J, Rich A, Kim KK, Jeon YH.; ''Solution structure of the Zbeta domain of human DNA-dependent activator of IFN-regulatory factors and its binding modes to B- and Z-DNAs.''; PubMed Europe PMC Scholia
- Zhang Z, Bao M, Lu N, Weng L, Yuan B, Liu YJ.; ''The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA.''; PubMed Europe PMC Scholia
- Zhang L, Mo J, Swanson KV, Wen H, Petrucelli A, Gregory SM, Zhang Z, Schneider M, Jiang Y, Fitzgerald KA, Ouyang S, Liu ZJ, Damania B, Shu HB, Duncan JA, Ting JP.; ''NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.''; PubMed Europe PMC Scholia
- Watson RO, Bell SL, MacDuff DA, Kimmey JM, Diner EJ, Olivas J, Vance RE, Stallings CL, Virgin HW, Cox JS.; ''The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy.''; PubMed Europe PMC Scholia
- Ha SC, Kim D, Hwang HY, Rich A, Kim YG, Kim KK.; ''The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA reveals an unusual binding mode to Z-DNA.''; PubMed Europe PMC Scholia
- Bonizzi G, Karin M.; ''The two NF-kappaB activation pathways and their role in innate and adaptive immunity.''; PubMed Europe PMC Scholia
- Li T, Diner BA, Chen J, Cristea IM.; ''Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16.''; PubMed Europe PMC Scholia
- Sauer JD, Sotelo-Troha K, von Moltke J, Monroe KM, Rae CS, Brubaker SW, Hyodo M, Hayakawa Y, Woodward JJ, Portnoy DA, Vance RE.; ''The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides.''; PubMed Europe PMC Scholia
- Orebaugh CD, Fye JM, Harvey S, Hollis T, Perrino FW.; ''The TREX1 exonuclease R114H mutation in Aicardi-Goutières syndrome and lupus reveals dimeric structure requirements for DNA degradation activity.''; PubMed Europe PMC Scholia
- Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T.; ''IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.''; PubMed Europe PMC Scholia
- Liu Y, Zou Z, Zhu B, Hu Z, Zeng P, Wu L.; ''LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes.''; PubMed Europe PMC Scholia
- Sun L, Wu J, Du F, Chen X, Chen ZJ.; ''Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.''; PubMed Europe PMC Scholia
- Li X, Massa PE, Hanidu A, Peet GW, Aro P, Savitt A, Mische S, Li J, Marcu KB.; ''IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program.''; PubMed Europe PMC Scholia
- Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, Chandran B.; ''IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection.''; PubMed Europe PMC Scholia
- Sharma S, Fitzgerald KA.; ''Innate immune sensing of DNA.''; PubMed Europe PMC Scholia
- Son KN, Liang Z, Lipton HL.; ''Double-Stranded RNA Is Detected by Immunofluorescence Analysis in RNA and DNA Virus Infections, Including Those by Negative-Stranded RNA Viruses.''; PubMed Europe PMC Scholia
- Gil J, Alcamí J, Esteban M.; ''Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex.''; PubMed Europe PMC Scholia
- Ma X, Helgason E, Phung QT, Quan CL, Iyer RS, Lee MW, Bowman KK, Starovasnik MA, Dueber EC.; ''Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation.''; PubMed Europe PMC Scholia
- Servant MJ, ten Oever B, LePage C, Conti L, Gessani S, Julkunen I, Lin R, Hiscott J.; ''Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3.''; PubMed Europe PMC Scholia
- Wang Z, Choi MK, Ban T, Yanai H, Negishi H, Lu Y, Tamura T, Takaoka A, Nishikura K, Taniguchi T.; ''Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules.''; PubMed Europe PMC Scholia
- Tanaka Y, Chen ZJ.; ''STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.''; PubMed Europe PMC Scholia
- Bowie AG, Unterholzner L.; ''Viral evasion and subversion of pattern-recognition receptor signalling.''; PubMed Europe PMC Scholia
- Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC Scholia
- Qin BY, Liu C, Lam SS, Srinath H, Delston R, Correia JJ, Derynck R, Lin K.; ''Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation.''; PubMed Europe PMC Scholia
- Ferguson BJ, Mansur DS, Peters NE, Ren H, Smith GL.; ''DNA-PK is a DNA sensor for IRF-3-dependent innate immunity.''; PubMed Europe PMC Scholia
- Clark K, Plater L, Peggie M, Cohen P.; ''Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation.''; PubMed Europe PMC Scholia
- Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J.; ''The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1.''; PubMed Europe PMC Scholia
- Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S.; ''The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA.''; PubMed Europe PMC Scholia
- Kaiser WJ, Upton JW, Mocarski ES.; ''Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors.''; PubMed Europe PMC Scholia
- Lee YH, Stallcup MR.; ''Interplay of Fli-I and FLAP1 for regulation of beta-catenin dependent transcription.''; PubMed Europe PMC Scholia
- Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V.; ''RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate.''; PubMed Europe PMC Scholia
- Jakobsen MR, Bak RO, Andersen A, Berg RK, Jensen SB, Tengchuan J, Laustsen A, Hansen K, Ostergaard L, Fitzgerald KA, Xiao TS, Mikkelsen JG, Mogensen TH, Paludan SR.; ''IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication.''; PubMed Europe PMC Scholia
- Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, Matsunaga K, Kageyama S, Omori H, Noda T, Yamamoto N, Kawai T, Ishii K, Takeuchi O, Yoshimori T, Akira S.; ''Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response.''; PubMed Europe PMC Scholia
- Paludan SR, Bowie AG.; ''Immune sensing of DNA.''; PubMed Europe PMC Scholia
- Sun W, Li Y, Chen L, Chen H, You F, Zhou X, Zhou Y, Zhai Z, Chen D, Jiang Z.; ''ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| 5'-ppp-AU-rich dsRNA | REACT_164072 (Reactome)  | ||
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| AGER [plasma membrane] | Protein | Q15109 (Uniprot-TrEMBL) | |
| AGER ligands:AGER | Complex | REACT_24620 (Reactome) | |
| APP(672-711)
[extracellular region] | Protein | P05067 (Uniprot-TrEMBL) | |
| APP(672-713)
[extracellular region] | Protein | P05067 (Uniprot-TrEMBL) | |
| AT-rich dsDNA | REACT_164924 (Reactome) | ||
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| Activated IKK Complex | Complex | REACT_7826 (Reactome) | |
| CBP/p300 | Protein | REACT_25880 (Reactome) | |
| CHUK [cytosol] | Protein | O15111 (Uniprot-TrEMBL) | |
| CREBBP(2-2442) [nucleoplasm] | Protein | Q92793 (Uniprot-TrEMBL) | |
| CTNNB1 [cytosol] | Protein | P35222 (Uniprot-TrEMBL) | |
| CTNNB1 | Protein | P35222 (Uniprot-TrEMBL) | |
| DDX41 [cytosol] | Protein | Q9UJV9 (Uniprot-TrEMBL) | |
| DDX41 ligand | Metabolite | REACT_160922 (Reactome) | |
| DDX41:DDX41 ligand | Complex | REACT_160900 (Reactome) | |
| DDX41 | Protein | Q9UJV9 (Uniprot-TrEMBL) | |
| DHX36 [cytosol] | Protein | Q9H2U1 (Uniprot-TrEMBL) | |
| DHX36:CpG:MyD88 | Complex | REACT_161245 (Reactome) | |
| DHX36:CpG | Complex | REACT_160366 (Reactome) | |
| DHX36 | Protein | Q9H2U1 (Uniprot-TrEMBL) | |
| DHX9 [cytosol] | Protein | Q08211 (Uniprot-TrEMBL) | |
| DHX9/DHX36:CpG:MyD88 | Complex | REACT_164459 (Reactome) | |
| DHX9/DHX36:CpG | Complex | REACT_165224 (Reactome) | |
| DHX9:CpG:MyD88 | Complex | REACT_160421 (Reactome) | |
| DHX9:CpG | Complex | REACT_164550 (Reactome) | |
| DHX9 | Protein | Q08211 (Uniprot-TrEMBL) | |
| DNA-PK:microbial dsDNA | Complex | REACT_161385 (Reactome) | |
| DTX4 [cytosol] | Protein | Q9Y2E6 (Uniprot-TrEMBL) | |
| DTX4 | Protein | Q9Y2E6 (Uniprot-TrEMBL) | |
| EP300(1-2414) [nucleoplasm] | Protein | Q09472 (Uniprot-TrEMBL) | |
| GTP | Metabolite | CHEBI:15996 (ChEBI) | |
| H2O | Metabolite | CHEBI:15377 (ChEBI) | |
| HMGB1 [extracellular region] | Protein | P09429 (Uniprot-TrEMBL) | |
| IFI16 [cytosol] | Protein | Q16666 (Uniprot-TrEMBL) | |
| IFI16 | Protein | Q16666 (Uniprot-TrEMBL) | |
| IKBKB [cytosol] | Protein | O14920 (Uniprot-TrEMBL) | |
| IKBKG [cytosol] | Protein | Q9Y6K9 (Uniprot-TrEMBL) | |
| IKKA:IKKB:NEMO | Complex | REACT_7693 (Reactome) | |
| IRF3 [cytosol] | Protein | Q14653 (Uniprot-TrEMBL) | |
| IRF3 | Protein | Q14653 (Uniprot-TrEMBL) | |
| IkBs:NFkB | Complex | REACT_7272 (Reactome) | |
| K48polyUb-DDX41 [cytosol] | Protein | Q9UJV9 (Uniprot-TrEMBL) | |
| K48polyUb-DDX41:TRIM21 | Complex | REACT_164901 (Reactome) | |
| K63polyUb-STING
[cytoplasmic vesicle membrane] | Protein | Q86WV6 (Uniprot-TrEMBL) | |
| K63polyUb-STING | Protein | Q86WV6 (Uniprot-TrEMBL) | |
| Ku70:Ku80 heterodimer | Complex | REACT_161331 (Reactome) | |
| LRR FLII-interacting protein 1 dimer | Complex | REACT_165504 (Reactome) | |
| LRRFIP1(1-808) [cytosol] | Protein | Q32MZ4 (Uniprot-TrEMBL) | |
| LZTS1 [cytosol] | Protein | Q9Y250 (Uniprot-TrEMBL) | |
| MB21D1 [cytosol] | Protein | Q8N884 (Uniprot-TrEMBL) | |
| MB21D1 | Protein | Q8N884 (Uniprot-TrEMBL) | |
| MRE11 ligand | REACT_165437 (Reactome) | ||
| MRE11:dsDNA | Complex | REACT_164808 (Reactome) | |
| MRE11A [cytosol] | Protein | P49959 (Uniprot-TrEMBL) | |
| MRE11A | Protein | P49959 (Uniprot-TrEMBL) | |
| MYD88 [cytosol] | Protein | Q99836 (Uniprot-TrEMBL) | |
| MYD88 | Protein | Q99836 (Uniprot-TrEMBL) | |
| Mg2+ [cytosol] | Metabolite | CHEBI:18420 (ChEBI) | |
| Mg2+ | Metabolite | CHEBI:18420 (ChEBI) | |
| N-epsilon-(1-(1-carboxy)ethyl)lysine
[extracellular region] | Metabolite | CHEBI:60125 (ChEBI) | |
| NECML [extracellular region] | Metabolite | CHEBI:53014 (ChEBI) | |
| NFKB1(1-433) [cytosol] | Protein | P19838 (Uniprot-TrEMBL) | |
| NFKB1(1-433) [nucleoplasm] | Protein | P19838 (Uniprot-TrEMBL) | |
| NFKB2(1-454) [cytosol] | Protein | Q00653 (Uniprot-TrEMBL) | |
| NFKB2(1-454) [nucleoplasm] | Protein | Q00653 (Uniprot-TrEMBL) | |
| NFKBIA [cytosol] | Protein | P25963 (Uniprot-TrEMBL) | |
| NFKBIB [cytosol] | Protein | Q15653 (Uniprot-TrEMBL) | |
| NFkB Complex | Complex | REACT_7108 (Reactome) | |
| NFkB Complex | Complex | REACT_7143 (Reactome) | |
| NLRP4 [cytosol] | Protein | Q96MN2 (Uniprot-TrEMBL) | |
| NLRP4:DTX4:p-S172-TBK1complexes | Complex | REACT_164593 (Reactome) | |
| NLRP4 | Protein | Q96MN2 (Uniprot-TrEMBL) | |
| POLR1C [cytosol] | Protein | O15160 (Uniprot-TrEMBL) | |
| POLR1D [cytosol] | Protein | Q9Y2S0 (Uniprot-TrEMBL) | |
| POLR2E [cytosol] | Protein | P19388 (Uniprot-TrEMBL) | |
| POLR2F(1-127) [cytosol] | Protein | P61218 (Uniprot-TrEMBL) | |
| POLR2H [cytosol] | Protein | P52434 (Uniprot-TrEMBL) | |
| POLR2K [cytosol] | Protein | P53803 (Uniprot-TrEMBL) | |
| POLR2L [cytosol] | Protein | P62875 (Uniprot-TrEMBL) | |
| POLR3A [cytosol] | Protein | O14802 (Uniprot-TrEMBL) | |
| POLR3B [cytosol] | Protein | Q9NW08 (Uniprot-TrEMBL) | |
| POLR3C [cytosol] | Protein | Q9BUI4 (Uniprot-TrEMBL) | |
| POLR3D [cytosol] | Protein | P05423 (Uniprot-TrEMBL) | |
| POLR3E [cytosol] | Protein | Q9NVU0 (Uniprot-TrEMBL) | |
| POLR3F [cytosol] | Protein | Q9H1D9 (Uniprot-TrEMBL) | |
| POLR3G [cytosol] | Protein | O15318 (Uniprot-TrEMBL) | |
| POLR3GL [cytosol] | Protein | Q9BT43 (Uniprot-TrEMBL) | |
| POLR3H [cytosol] | Protein | Q9Y535 (Uniprot-TrEMBL) | |
| POLR3K [cytosol] | Protein | Q9Y2Y1 (Uniprot-TrEMBL) | |
| PPi | Metabolite | CHEBI:29888 (ChEBI) | |
| PRKDC(2-4128) [cytosol] | Protein | P78527 (Uniprot-TrEMBL) | |
| PRKDC(2-4128) | Protein | P78527 (Uniprot-TrEMBL) | |
| Peptide
[extracellular region] | Metabolite | CHEBI:16670 (ChEBI) | |
| Phospho-NF-kappaB Inhibitor | REACT_7645 (Reactome) | ||
| Promotor region of interferon beta | REACT_25836 (Reactome) | ||
| RELA [cytosol] | Protein | Q04206 (Uniprot-TrEMBL) | |
| RELA [nucleoplasm] | Protein | Q04206 (Uniprot-TrEMBL) | |
| RIG-I/MDA5 mediated
induction of IFN-alpha/beta pathways | Pathway | WP1904 (WikiPathways) | RIG-I-like helicases (RLHs) the retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) are RNA helicases that recognize viral RNA present within the cytoplasm. Functionally RIG-I and MDA5 positively regulate the IFN genes in a similar fashion, however they differ in their response to different viral species. RIG-I is essential for detecting influenza virus, Sendai virus, VSV and Japanese encephalitis virus (JEV), whereas MDA5 is essential in sensing encephalomyocarditis virus (EMCV), Mengo virus and Theiler's virus, all of which belong to the picornavirus family. RIG-I and MDA5 signalling results in the activation of IKK epsilon and (TKK binding kinase 1) TBK1, two serine/threonine kinases that phosphorylate interferon regulatory factor 3 and 7 (IRF3 and IRF7). Upon phosphorylation, IRF3 and IRF7 translocate to the nucleus and subsequently induce interferon alpha (IFNA) and interferon beta (IFNB) gene transcription. |
| RIPK1 [cytosol] | Protein | Q13546 (Uniprot-TrEMBL) | |
| RIPK1 [endosome membrane] | Protein | Q13546 (Uniprot-TrEMBL) | |
| RIPK1 | Protein | Q13546 (Uniprot-TrEMBL) | |
| RIPK3 [cytosol] | Protein | Q9Y572 (Uniprot-TrEMBL) | |
| RIPK3 | Protein | Q9Y572 (Uniprot-TrEMBL) | |
| RNA Polymerase III Holoenzyme | Complex | REACT_164450 (Reactome) | |
| S100A12
[extracellular region] | Protein | P80511 (Uniprot-TrEMBL) | |
| S100B [extracellular region] | Protein | P04271 (Uniprot-TrEMBL) | |
| SAA1(19-122)
[extracellular region] | Protein | P0DJI8 (Uniprot-TrEMBL) | |
| STAT6 [cytosol] | Protein | P42226 (Uniprot-TrEMBL) | |
| STAT6 | Protein | P42226 (Uniprot-TrEMBL) | |
| STING activators | Complex | REACT_164315 (Reactome) | |
| STING:STING | Complex | REACT_148482 (Reactome) | |
| STING:STING | Complex | REACT_160695 (Reactome) | |
| STING:TBK1:IRF3 | Complex | REACT_148249 (Reactome) | |
| STING:TBK1:STAT6 | Complex | REACT_165575 (Reactome) | |
| STING:TRIM32/TRIM56 | Complex | REACT_164587 (Reactome) | |
| STING:c-di-GMP | Complex | REACT_147998 (Reactome) | |
| STING:cGAMP | Complex | REACT_165414 (Reactome) | |
| STING:p-S172-TBK1:IRF3 | Complex | REACT_148605 (Reactome) | |
| STING:p-S172-TBK1:STAT6 | Complex | REACT_164288 (Reactome) | |
| STING:p-S172-TBK1 | Complex | REACT_148607 (Reactome) | |
| TBK1 [cytosol] | Protein | Q9UHD2 (Uniprot-TrEMBL) | |
| TBK1 | Protein | Q9UHD2 (Uniprot-TrEMBL) | |
| TICAM1 [endosome membrane] | Protein | Q8IUC6 (Uniprot-TrEMBL) | |
| TLR3 [endosome membrane] | Protein | O15455 (Uniprot-TrEMBL) | |
| TMEM173 [endoplasmic reticulum membrane] | Protein | Q86WV6 (Uniprot-TrEMBL) | |
| TMEM173 | Protein | Q86WV6 (Uniprot-TrEMBL) | |
| TMP | Metabolite | CHEBI:17013 (ChEBI) | |
| TREX1 [endoplasmic reticulum membrane] | Protein | Q9NSU2 (Uniprot-TrEMBL) | |
| TREX1 dimer | Complex | REACT_165268 (Reactome) | |
| TREX1:viral DNA | Complex | REACT_164408 (Reactome) | |
| TRIM21 [cytosol] | Protein | P19474 (Uniprot-TrEMBL) | |
| TRIM21 | Protein | P19474 (Uniprot-TrEMBL) | |
| TRIM32 [cytosol] | Protein | Q13049 (Uniprot-TrEMBL) | |
| TRIM32/TRIM56 | Protein | REACT_165399 (Reactome) | |
| TRIM56 [cytosol] | Protein | Q9BRZ2 (Uniprot-TrEMBL) | |
| Ub | Protein | REACT_3316 (Reactome) | |
| Unmethylated CpG DNA | REACT_161474 (Reactome) | ||
| XRCC5 [cytosol] | Protein | P13010 (Uniprot-TrEMBL) | |
| XRCC6 [cytosol] | Protein | P12956 (Uniprot-TrEMBL) | |
| ZBP1 [cytosol] | Protein | Q9H171 (Uniprot-TrEMBL) | |
| ZBP1 | Protein | Q9H171 (Uniprot-TrEMBL) | |
| bacterial dsDNA | REACT_160413 (Reactome) | ||
| beta-catenin:IRF3:p300 | Complex | REACT_164162 (Reactome) | |
| c-GMP-AMP [cytosol] | Metabolite | CHEBI:71580 (ChEBI) | |
| c-GMP-AMP | Metabolite | CHEBI:71580 (ChEBI) | |
| c-di-AMP [cytosol] | Metabolite | CHEBI:47037 (ChEBI) | |
| c-di-GMP [cytosol] | Metabolite | CHEBI:49537 (ChEBI) | |
| c-di-GMP | Metabolite | CHEBI:49537 (ChEBI) | |
| cGAS ligand | Metabolite | REACT_165334 (Reactome) | |
| cGAS:dsDNA | Complex | REACT_164787 (Reactome) | |
| dAMP | Metabolite | CHEBI:17713 (ChEBI) | |
| dCMP | Metabolite | CHEBI:15918 (ChEBI) | |
| dGMP | Metabolite | CHEBI:16192 (ChEBI) | |
| dsDNA:IFI16 | Complex | REACT_148075 (Reactome) | |
| dsDNA:LRR
FLII-interacting protein 1dimer | Complex | REACT_165341 (Reactome) | |
| dsDNA:LRRFIP1:beta-catenin | Complex | REACT_164918 (Reactome) | |
| dsDNA:ZBP1:RIP1:RIP3 | Complex | REACT_116701 (Reactome) | |
| dsDNA:ZBP1:pS-172-TBK1 | Complex | REACT_119373 (Reactome) | |
| dsDNA:ZBP1:pS-172-TBK:IRF3 | Complex | REACT_118875 (Reactome) | |
| dsDNA:ZBP1 | Complex | REACT_116520 (Reactome) | |
| microbial dsDNA | Metabolite | REACT_160598 (Reactome) | |
| p-2S-IRF7:p-2S-IRF7 | Complex | REACT_21640 (Reactome) | |
| p-2S-IRF7:p-2S-IRF7 | Complex | REACT_21965 (Reactome) | |
| p-4S,T404-IRF3 [cytosol] | Protein | Q14653 (Uniprot-TrEMBL) | |
| p-4S,T404-IRF3 [nucleoplasm] | Protein | Q14653 (Uniprot-TrEMBL) | |
| p-4S,T404-IRF3 | Protein | Q14653 (Uniprot-TrEMBL) | |
| p-S172,K48polyUb-TBK1 complexes | Complex | REACT_164137 (Reactome) | |
| p-S172-TBK1 [cytosol] | Protein | Q9UHD2 (Uniprot-TrEMBL) | |
| p-S172-TBK1 complexes | Complex | REACT_165211 (Reactome) | |
| p-S176,S180-CHUK [cytosol] | Protein | O15111 (Uniprot-TrEMBL) | |
| p-S177,S181-IKBKB [cytosol] | Protein | O14920 (Uniprot-TrEMBL) | |
| p-S407,Y641-STAT6 [cytosol] | Protein | P42226 (Uniprot-TrEMBL) | |
| p-S407,Y641-STAT6 [nucleoplasm] | Protein | P42226 (Uniprot-TrEMBL) | |
| p-S407,Y641-STAT6 dimer | Complex | REACT_164683 (Reactome) | |
| p-S407,Y641-STAT6 dimer | Complex | REACT_165571 (Reactome) | |
| p-S407,Y641-STAT6 | Protein | P42226 (Uniprot-TrEMBL) | |
| p-S407-STAT6 | Protein | P42226 (Uniprot-TrEMBL) | |
| p-S477,S479-IRF7 [cytosol] | Protein | Q92985 (Uniprot-TrEMBL) | |
| p-S477,S479-IRF7 [nucleoplasm] | Protein | Q92985 (Uniprot-TrEMBL) | |
| p-S552-CTNNB1 [nucleoplasm] | Protein | P35222 (Uniprot-TrEMBL) | |
| p-S552-CTNNB1 | Protein | P35222 (Uniprot-TrEMBL) | |
| p-T,4S-IRF3:p-T,4S-IRF3 | Complex | REACT_7146 (Reactome) | |
| p-T,4S-IRF3:p-T,4S-IRF3 | Complex | REACT_7444 (Reactome) | |
| viral dsRNA:TLR3:TRIF:RIP1 | Complex | REACT_7715 (Reactome) | |
| viral DNA with 3' sticky ends | Complex | REACT_8181 (Reactome) | |
| viral dsDNA | REACT_161032 (Reactome) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 5'-ppp-AU-rich dsRNA | Arrow | REACT_163897 (Reactome) | ||
| ADP | Arrow | REACT_118685 (Reactome) | ||
| ADP | Arrow | REACT_118783 (Reactome) | ||
| ADP | Arrow | REACT_147769 (Reactome) | ||
| ADP | Arrow | REACT_147901 (Reactome) | ||
| ADP | Arrow | REACT_163707 (Reactome) | ||
| ADP | Arrow | REACT_163766 (Reactome) | ||
| ADP | Arrow | REACT_163774 (Reactome) | ||
| ADP | Arrow | REACT_163955 (Reactome) | ||
| ADP | Arrow | REACT_6848 (Reactome) | ||
| ADP | Arrow | REACT_6973 (Reactome) | ||
| AGER ligands:AGER | Arrow | REACT_6906 (Reactome) | ||
| AT-rich dsDNA | REACT_163897 (Reactome) | |||
| ATP | REACT_118685 (Reactome) | |||
| ATP | REACT_118783 (Reactome) | |||
| ATP | REACT_147769 (Reactome) | |||
| ATP | REACT_147901 (Reactome) | |||
| ATP | REACT_163707 (Reactome) | |||
| ATP | REACT_163766 (Reactome) | |||
| ATP | REACT_163774 (Reactome) | |||
| ATP | REACT_163779 (Reactome) | |||
| ATP | REACT_163955 (Reactome) | |||
| ATP | REACT_6848 (Reactome) | |||
| ATP | REACT_6973 (Reactome) | |||
| Activated IKK Complex | Arrow | REACT_6973 (Reactome) | ||
| Activated IKK Complex | mim-catalysis | REACT_6848 (Reactome) | ||
| CBP/p300 | REACT_163902 (Reactome) | |||
| CTNNB1 | REACT_163821 (Reactome) | |||
| DDX41 ligand | REACT_163653 (Reactome) | |||
| DDX41:DDX41 ligand | Arrow | REACT_163653 (Reactome) | ||
| DDX41 | REACT_163639 (Reactome) | |||
| DDX41 | REACT_163653 (Reactome) | |||
| DHX36:CpG:MyD88 | Arrow | REACT_24920 (Reactome) | ||
| DHX36:CpG | Arrow | REACT_163740 (Reactome) | ||
| DHX36 | REACT_163740 (Reactome) | |||
| DHX9/DHX36:CpG:MyD88 | Arrow | REACT_163991 (Reactome) | ||
| DHX9/DHX36:CpG | REACT_163991 (Reactome) | |||
| DHX9:CpG:MyD88 | Arrow | REACT_6906 (Reactome) | ||
| DHX9:CpG | Arrow | REACT_163771 (Reactome) | ||
| DHX9 | REACT_163771 (Reactome) | |||
| DNA-PK:microbial dsDNA | Arrow | REACT_163719 (Reactome) | ||
| DTX4 | Arrow | REACT_163856 (Reactome) | ||
| DTX4 | REACT_163683 (Reactome) | |||
| GTP | REACT_163779 (Reactome) | |||
| H2O | REACT_163957 (Reactome) | |||
| IFI16 | REACT_147878 (Reactome) | |||
| IKKA:IKKB:NEMO | REACT_6973 (Reactome) | |||
| IRF3 | REACT_118613 (Reactome) | |||
| IRF3 | REACT_147703 (Reactome) | |||
| IkBs:NFkB | REACT_6848 (Reactome) | |||
| K48polyUb-DDX41:TRIM21 | Arrow | REACT_163639 (Reactome) | ||
| K63polyUb-STING | Arrow | REACT_163749 (Reactome) | ||
| Ku70:Ku80 heterodimer | REACT_163719 (Reactome) | |||
| LRR FLII-interacting protein 1 dimer | REACT_163915 (Reactome) | |||
| MB21D1 | REACT_163636 (Reactome) | |||
| MRE11 ligand | REACT_163772 (Reactome) | |||
| MRE11:dsDNA | Arrow | REACT_163772 (Reactome) | ||
| MRE11A | REACT_163772 (Reactome) | |||
| MYD88 | REACT_163991 (Reactome) | |||
| Mg2+ | REACT_163654 (Reactome) | |||
| NFkB Complex | Arrow | REACT_6848 (Reactome) | ||
| NFkB Complex | Arrow | REACT_6906 (Reactome) | ||
| NFkB Complex | REACT_6906 (Reactome) | |||
| NLRP4:DTX4:p-S172-TBK1complexes | Arrow | REACT_163683 (Reactome) | ||
| NLRP4:DTX4:p-S172-TBK1complexes | REACT_163856 (Reactome) | |||
| NLRP4:DTX4:p-S172-TBK1complexes | TBar | REACT_118685 (Reactome) | ||
| NLRP4:DTX4:p-S172-TBK1complexes | TBar | REACT_147769 (Reactome) | ||
| NLRP4:DTX4:p-S172-TBK1complexes | mim-catalysis | REACT_163856 (Reactome) | ||
| NLRP4 | Arrow | REACT_163856 (Reactome) | ||
| NLRP4 | REACT_163683 (Reactome) | |||
| PPi | Arrow | REACT_163779 (Reactome) | ||
| PRKDC(2-4128) | REACT_163719 (Reactome) | |||
| Phospho-NF-kappaB Inhibitor | Arrow | REACT_6848 (Reactome) | ||
| Promotor region of interferon beta | REACT_163902 (Reactome) | |||
| REACT_118567 (Reactome) | IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm. | |||
| REACT_118613 (Reactome) | ZBP1 (DAI) dimer formation enables recruitment of TBK1 and IRF3 to the C-terminal region of DAI in response to cytosolic DNA in murine L929 cells. This interaction is DNA-dependent as ZBP1(DAI) mutants that lack DNA binding domains neither recruited TBK1 nor activated IRF3 (Takaoka A et al 2007). Activation of IRF-3 and possibly IRF-7 promotes IFN gene expression. | |||
| REACT_118621 (Reactome) | ZBP1(DAI) binds to double-stranded DNA in vitro and in vivo (Wang ZC et al 2008; Takaoka A et al 2007). N-teminus of ZBP1 contains two Z-DNA (Zalpha and Zbeta) and one B-DNA binding domains (D3 region). D3 region mediates initial binding of ZBP1 to DNA with subsequent stabilization provided by the Zalpha and Zbeta domains. All tree DNA-binding domains are required for ZBP1 full activation (Wang ZC et al 2008). ZBP1 was reported to form multimer upon DNA binding that might facilitate innate immune responces (Wang ZC et al 2008; Ha SC et al 2008). | |||
| REACT_118685 (Reactome) | IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring Ser386 and/or Ser385- site 1; and a cluster of serine/threonine residues between Ser396 and Ser405- site 2 [Panne et al 2007]. Phosphorylated residues at site 2 (Ser396 - Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). Phosphorylation at site 1 is required for IRF3 dimerization. | |||
| REACT_118783 (Reactome) | ZBP1 (DAI) dimer formation enables recruitment of TBK1 and IRF3 to the C-terminal region of DAI in response to cytosolic DNA in murine L929 cells. This interaction is DNA-dependent as ZBP1(DAI) mutants that lack DNA binding domains neither recruited TBK1 nor activated IRF3 (Takaoka A et al 2007). Activation of IRF-3 and possibly IRF-7 promotes IFN gene expression. | |||
| REACT_118851 (Reactome) | Two RIP homotypic interaction motifs (RHIM) were identified in the DAI protein sequence. These two domains were shown to be essential for DAI-induced NFkB activation in human embryonic kidney 293T (HEK293T) cells. DAI forms a complex with two RHIM-containing kinases - RIP1 and RIP3 (Kaiser WJ et al 2008, Rebsamen M et al 2009). Recruitment of RIP3 to DAI was reported to induce RIP3 autophosphorylation. Furthermore, knockdown of RIP1 or RIP3 affected DAI-induced NFkB signals in murine L929 fibroblast and human HEK293T cells (Kaiser WJ et al 2008, Rebsamen M et al 2009). | |||
| REACT_147703 (Reactome) | In dsDNA-stimulated human and mouse cells TBK1 has been shown to move to cytoplasmic punctate structures, where it associates with STING to induce IRF3 activation [Ishikawa H et al. 2009; Saitoh T et al. 2009; Sun W et al. 2009; Tanaka Y and Chen ZJ 2012]. Co-immunoprecipitation assays in HEK 293T cells expressing HA-tagged STING and Flag-tagged TBK1 showed that TBK1 directly interacts with STING. Moreover, glutathione S-transferase (GST) pull-down assays showed that recruitment of TBK1 by STING was enhanced upon c-di-GMP binding [Ouyang S et al. 2012]. STING was reported to mediate TBK1-dependent activation of transcription factor IRF3 [Zhong B et al. 2008; Tanaka Y and Chen ZJ 2012]. Both TBK1 and IRF3 can directly interact with STING through its C-terminal region [Tanaka Y and Chen ZJ 2012]. A construct of human STING containing only 39 amino acid residues of its C-terminus (341 to 379) was sufficient to activate IRF3 in cytosolic extracts of HeLa cells. Further mutagenesis studies showed, that two residues, Ser366 and Leu374, within the C-terminal tail of STING were required for IRF3 binding and phosphorylation, but were dispensable for TBK1 binding and activation [Tanaka Y and Chen ZJ 2012]. Thus, STING is thought to function as a scaffold to recruit cytosolic TBK1 and IRF3, which results in TBK1-dependent phosphorylation of IRF3. in TBK1dependent phosphorylation of IRF3. Importantly, though both monomer and dimer STING can bind TBK1, only STING dimer binds TBK1 and activates Type I IFN [Ouyang S et al. 2012]. | |||
| REACT_147763 (Reactome) | Cyclic di-GMP (c-di-GMP) and cyclic-di-AMP (c-di-AMP) are ubiquitous secondary messengers secreted by bacteria, but not by eukarya. UV cross-linking experiment with radiolabeled c-di-GMP in lysates of human embryonic kidney 293T (HEK293T) cells expressing mouse Sting showed that STING recognizes and directly binds to c-di-GMP [Burdette DL et al 2011]. STING was reported to contain multiple trans-membrane regions at its N-terminus while its C-terminal domain (CTD) is cytosolic. Mutational analysis showed that the CTD is responsible for the binding to c-di-GMP and this binding enhances the recruitment of TBK1 by STING [Ouyang S et al 2012]. Furthermore, a C-terminal tail (CTT) within the CTD interacts with and activates TBK1 and IRF3 [Tanaka Y and Chen ZJ 2012]. Impotantly, Sting is required for both c-di-GMP and c-di-AMP induced type I IFN production in mouse cultured macrophages infected with intracellular pathogens in vitro [Jin L et al 2011; Sauer JD et al 2011]. Low levels of STING protein expressed in human embryonic kidney (HEK293T) cells were sufficient to reconstitute the responsiveness of the cells to both c-di-GMP and c-di-AMP [Burdette DL et al 2011]. However, structural studies of STING revealed, that STING prefers c-di-GMP over c-di-AMP [Ouyang S et al 2012]. Several studies have demonstrated that human STING functions as a dimer and STING dimerization was essential for the induction of IFN response [Sun W et al 2009; Burdette DL et al 2011; Jin L et al 2011; Ouyang S et al 2012]. Mouse Sting/Myps has been also reported to exist as a dimer constitutively [Jin L et al 2008]. Moreover, STING can function as a ROS sensor, which forms a disulfide-linked homodimer under conditions of oxidative stress in HEK293T cells [Jin L et al 2010]. Structure analysis of the C-terminal domain in complex with c-di-GMP revealed that two STING molecules associate with one molecule of c-di-GMP [Ouyang S et al 2012; Yin Q et al 2012; Scu C et al 2012]. The STING dimer is thought to have a V-shaped structure, and the c-di-GMP binding site is located at the bottom of the V of the dimer interface [Scu C et al 2012]. Isothermal titration calorimetry (ITC) experiments confirmed the stoichiometry of STING to c-di-GMP as 2:1 with a binding dissociation constant (Kd) of ~2.4 microM [Yin Q et al 2012; Scu C et al 2012]. The data are consistent with a previous measurement of mouse STING CTD binding affinity to c-di-GMP using equilibrium dialysis [Burdette DL et al 2011]. Although STING is considered as a direct sensor of bacterial c-di-GMP, it is noteworthy, that the binding affinity of c-di-GMP to mammalian STING is much weaker than to bacterial sensors. For example, E.coli protein YcgR binds to c-di-GMP with a Kd of ~0.84 microM [Ryjenkov DA et al 2006]. Also taking into account that, the normal concentration of c-di-GMP in bacteria varies from 0.1~10 microM, it remains to be determined whether STING binds to c-di-GMP under physiological conditions. | |||
| REACT_147769 (Reactome) | IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring Ser386 and/or Ser385- site 1; and a cluster of serine/threonine residues between Ser396 and Ser405- site 2 [Panne et al 2007]. Phosphorylated residues at site 2 (Ser396 - Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). Phosphorylation at site 1 is required for IRF3 dimerization. | |||
| REACT_147821 (Reactome) | IRF3 phosphorylation promotes IRF3 dimerization and nuclear translocation, which results in the production of type I interferons (IFNs). | |||
| REACT_147878 (Reactome) | Interferon (IFN)-inducible IFI16 protein was shown to be critical for type I IFN and pro inflammatory responses in viral DNA-stimulated human and mouse cells [Unterholzner L et al 2010; Kerur N et al 2011; Li T et al 2012]. Despite being predominantly nuclear, IFI16 can sense pathogenic DNA in both the cytoplasm and the nucleus. Cytosolic IFI16 can directly bind viral dsDNA motifs via its HIN200 domains in human monocytic leukemia THP-1 cell extracts. IFI16-mediated response to cytosolic DNA was reported to induce type I IFN production in a STING-TBK1- and IRF3 dependent manner [Unterholzner L et al 2010]. Nuclear IFI16 can detect kaposi sarcoma-associated herpesvirus (KSHV) DNA which results in IL-1beta maturation and caspase-1 inflammasome activation in human cells [Kerur N et al 2011]. Importantly, acetylation of the nuclear localization signal (NLS) of IFI16 in lymphocytes and macrophages leads to cytosolic accumulation of IFI16 and is important for its type I IFN stimulation ability in cytoplasm [Li T et al 2012]. | |||
| REACT_147901 (Reactome) | TBK1 activity is regulated by phosphorylation of Ser-172 within the kinase activation loop [Kishore N et al 2002]. TBK1 phosphorylation is thought to be an autoactivation event. Biochemical analysis demonstrated that the kinase domain alone was sufficient to fully autoactivate TBK1 and was capable of phosphorylating both macromolecular and peptide substrates [Ma X et al 2012]. Furthermore, TBK1 can autophosphorylate at Ser-172 and autoactivate when overexpressed in HEK293 cells. Additionally, in co-transfection experiments wild type TBK1 associated with and phosphorylated the catalytically inactive mutant TBK1-(K38A) at Ser-172 [Clark K et al 2009]. Studies of the crystal structure of TBK1 in complex with a potent small-molecule inhibitor BX795 revealed that Ser-172 from one protomer is located in close proximity to the active site of the neighboring protomer, providing a snapshot of a potential transautoactivation reaction intermediate [Ma X et al 2012]. However, involvement of a distinct upstream activating kinase in the TBK1 phosphorylation should not be ruled out [Clark K et al 2009]. | |||
| REACT_163630 (Reactome) | Several studies have demonstrated that human STING functions as a dimer and STING dimerization was essential for the induction of IFN response (Sun W et al. 2009; Burdette DL et al. 2011; Jin L et al. 2011; Ouyang S et al. 2012). Mouse Sting/Myps has been also reported to exist as a dimer constitutively [Jin L et al 2008]. Moreover, STING can function as a ROS sensor, which forms a disulfide-linked homodimer under conditions of oxidative stress in HEK293T cells [Jin L et al 2010]. Structural studies revealed that the strictly conserved cytosolic aa 153-173 region of STING participates in dimerization via hydrophobic interactions (Ouyang S et al. 2012). STING was shown to undergo K63-linked ubiquitination, which may facilitate its dimerization (Tsuchid T et al. 2010; Zhang J et al. 2012) | |||
| REACT_163636 (Reactome) | Cyclic GMP-AMP (cGAMP) synthase (cGAS) was identified as a cytosolic DNA sensor, which induced STING-mediated induction of type I interferon (Sun L et al. 2013). Knockdown of cGAS inhibited IRF3 activation and IFN-beta production in human acute monocytic leukemia cell line (THP1) in response to DNA transfection or DNA virus infection. Affinity-purified human or mouse cGAS proteins from transfected human embryonic kidney HEK293T cells were able to catalyze the production of cGAMP in vitro, which stimulated IRF3 dimerization in mouse Raw264.7 cells (mouse Abelson murine leukemia virus-induced tumor cell line). The catalytic activity of cGAS was shown to depend on the presence of DNA (Sun L et al. 2013). Sun L et al. suggested that sGAS acts as a cytosolic DNA sensor, which triggers type I interferon induction by producing the second messenger cGAMP in mammalian cells. | |||
| REACT_163639 (Reactome) | TRIM21 (Ro52/SSA1) is a member of the TRIM (Tripartite Motif) family of E3 ligases. E3 activity of TRIM21 was found to be a RING domain-dependent and required E2-conjugating enzymes UBE2D1/2/3/4 and UBE2E1/2 (Espinosa A et al. 2011). TRIM21 can form a complex with DDX41 leading to the K48-linked ubiquitination and degradation of DDX41 (Zhang Z et al. 2013). | |||
| REACT_163653 (Reactome) | The helicase DDX41 was shown to sense exogenous DNA in human and mouse cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 was also reported to sense and interact with bacterial secondary messengers cyclic di-GMP or cyclic di-AMP (Parvatiyar K et al. 2012). Mutagenesis analysis with DDX41 deletion constructs revealed that the central DEAD-box domain of DDX41 mediated the binding with DNA (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Knockdown of DDX41 or STING in human cells (THP-1 and PBMC cells) and mouse dendritic cells significantly reduced the cytokine production in response to pathogen-derived DNA or poly(dG:dC) (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 localized together with STING in the cytoplasm when both DDX41 and STING were co-expressed in HEK293T cells (Zhang Z et al. 2011). Mouse Ddx41 was found to bind Sting and Tbk1 in both resting and poly(dA:dT)-stimulated mouse splenic myeloid dendritic cell (D2SC mDCs) (Zhang Z et al. 2011). Ddx41-Sting interaction was also observed in c-di-GMP- or c-di-AMP-treated D2SC cells (Parvatiyar K et al. 2012). Moreover, knockdown of Ddx41 or Sting inhibited phosphorylation of Tbk1, Irf3, p65 subunit of NF-kappaB and other signal transducers in DNA-stimulated mouse bone marrow-derived (BMDCs) and D2SC cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Collectively, these data suggest that DNA triggers DDX41 downstream signaling to type I interferon in a STING-dependent manner. The E3 ubiquitin ligase TRIM21 was reported to promote the K48-linked ubiquitination and degradation of DDX41 leading to downregulation of the type I interferon production in mouse mDC and human monocytes THP-1 (Zhang Z et al. 2013). | |||
| REACT_163654 (Reactome) | TREX1 was shown to bind and degrade the HIV DNA fragments, which were generated during reverse transcription in HIV-infected human cells (Yan N et al. 2010). Other studies showed that TREX1 may regulate host responses to infection with several different types of RNA viruses (Hasan M et al. 2012). TREX1 is thought to clear viral derived DNA from the cytoplasm and thereby inhibit the activation of cytosolic DNA sensors (Yan N et al. 2010; Hasan M et al. 2012). Structural studies of the human and mouse TREX proteins revealed the dimeric nature of the TREX family exonucleases (Brucet M et al. 2007; de Silva U et al. 2007, 2009; Perrino FW et al. 2005; Bailey SL et al 2012). Besides, the stable TREX1 dimer was purified from bacterial cells expressing affinity-tagged human TREX1 proteins (Orebaugh CD et al. 2011).Comparative structural analysis of wild type (wt) and natural mutant variants of TREX1 in complex with ssDNA provided some insights into mechanism of the TREX1 exonuclease activity (Bailey SL et al 2012). The reaction begins with the binding of metal ions and DNA substrate in the enzyme active site, which results in the transition of catalytic histidine residue H195 from a disordered to an ordered state. The distance between two divalent metal ions is also essential for catalytic activity. The authors proposed a mechanism where the two protomers in TREX1 dimer alternate back and forth between active and resting states as they degrade substrate. The activity status is mediated by the dual conformation of H195, which is coordinated with the shift of the metal ion from 3.1 A when H195 is out of the active site (resting) to 3.6 A when H195 moves into the active site (active) (Bailey SL et al 2012). In addition, the structures of the TREX1 mutant proteins (dominant D200H, D200N and D18N homodimer mutants derived from AGS and FCL patients, as well as the recessive V201D mutant) provided insight into the dysfunction relating to human diseases (Bailey SL et al. 2012). The comparative analysis of the exonuclease activity of the dominant mutant TREX1 proteins (homo- and heterodimers generated from wt- and mutant TREX1 monomers) are in agreement with findings of Bailey et al.(Lehtinen DA et al. 2008; Fye JM et al. 2011; Bailey SL et al. 2012). | |||
| REACT_163667 (Reactome) | Endogenous STAT6 was found to co-fractionate with STING from the lysates of Herpes simplex virus 1 (HSV-1) - infected HeLa cells. Similar results were obtained from Sendai virus (SeV)-infected HeLa cells, where STAT6 redistributed to the perinuclear region to co-localizes with STING upon infection. Co-immunoprecipitation assays confirmed STAT6-STING interaction in human embryonic kidney HEK293 cells. The DNA-binding domain (DBD) of STAT6 and C terminus (aa 317-379) of STING were essential for this interaction. The TBK1 kinase activity was required for virus-induced STAT6 phosphorylation, however the direct interaction between STAT6 and TBK1 is not yet reported (Chen H et al. 2011). Co-immunoprecipitation assays in HEK293T cells expressing HA-tagged STING and Flag-tagged TBK1 showed that TBK directly interacts with STING (Ouyang S et al. 2012). | |||
| REACT_163668 (Reactome) | Phosphorylation of STAT6 results in the homodimerization and nucleus translocation of STAT6 where it binds to the target sites to initiate transcription. | |||
| REACT_163683 (Reactome) | NLRP4 (or NACHT, LRR and PYD domains-containing protein 4) and E3 ubiquitin-protein ligase DTX4 were reported to regulate the activation of type I interferon induced by double-stranded RNA or DNA (Cui J et al. 2012). Co-transfection with various combinations of full-length and truncated NLRP4 and DTX4 proteins in human embryonic kidney HEK293T cells, followed by IFN-signaling reporter assays and immunoassays showed that Nod domain of NLRP4 regulated TBK1 activity by recruiting DTX4 through the RING domain to the kinase domain of TBK1. The E3-ligase activity of DTX4 promoted K48-linked ubiquitination of TBK1 targeting it to the proteosomal degradation.The NLRP4 and DTX4 knockdown by siRNA in peripheral blood mononuclear cells (PBMCs) and THP-1 cells resulted in higher type I interferon production following stimulation with vesicular stomatitis virus (VSV), Sendai virus, and transfected Poly(dA:dT), which may engage various cytosolic receptors to activate IFN regulatory factor 3 (IRF3) downstream of TBK1 (Cui J et al. 2012). | |||
| REACT_163707 (Reactome) |
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| REACT_163719 (Reactome) | DNA-dependent serine/threonine protein kinase DNA-PK is a DNA damage sensor, which is composed of a large catalytic subunit DNA-PKcs and a heterodimer of Ku70 & Ku80 subunits. DNA-PK was found both in the nucleus and in the cytosol (Lucero H et al. 2003). While in the nucleus DNA-PK is critical for the repair of double-stranded DNA breaks during the lymphocyte development, in the cytosol it can also bind DNA fragments to transmit stress signals (Dip R & Naegeli H 2005; Yotsumoto S et al. 2008; Dragoi AM et al. 2004; Ferguson BJ et al. 2012). This Reactome event presents DNA-PK as a holoenzyme, however it remains unclear whether all DNA-PK subunits are critical for exogenous DNA recognition, whether they function as a DNA-PK complex or each subunit acts independently in certain circumstances (Zhang X et al. 2011; Ferguson BJ et al. 2012). Studies involving different human and mouse cell lines yielded variable results regarding to DNA-PK signaling functions. The catalytic subunit DNA-PKcs has been shown to associate with Akt upon CpG-OND-stimulation triggering transient nuclear translocation of Akt in mouse bone marrow-derived macrophages (BMDMs)(Dragoi AM et al. 2004). DNA-PKcs has been also reported to induce ERK activation and production of anti-inflammatory cytokine IL-10 in CpG-ODN-stimulated mouse monocyte/macrophage cell line RAW264.7, while production of pro-inflammatory cytokine IL-12 was negatively regulated (Yotsumoto S et al. 2008). In addition, endosomal translocation of CpG-ODN was found to regulate DNA-PKcs-mediated responses to CpG-OND (Yotsumoto S et al. 2008; Hazeki K et al. 2011). Moreover, DNA-PK subunits have been implicated in IFN regulatory factor (IRF)-dependent innate immune responses. Ku-70 was shown to induce production of type III IFN (IFN -lamda 1) in human embryonic kidney HEK293 cells transfected with DNA. The Ku70-mediated IFN-lamda 1 activation required a longer size of DNA (>500 bp DNA) (Zhang X et al. 2011). Whether DNA-PK mediates activation of IFN-beta production is debatable. Ku70- or DNA-PKcs-deficient mouse bone marrow-derived macrophages cells mounted an identical IFN-beta response when compared to their wild-type controls (Stetson DB & Medzhitov R 2006). However, the other group demonstrated that DNA-PK induced IRF3-dependent production of IFN-beta in DNA-stimulated mouse embryonic fibroblast(MEF) and human HEK293 cells (Ferguson BJ et al. 2012). Thus, the molecular mechanism behind DNA-PK activation by cytosolic DNA remains to be clarified. It's interesting to note that in the nucleus DNA-PK may regulate IRF3 transcriptional activity in response to viral infection. DNA-PK was found to bind and phosphorylate IRF-3 at Thr-135 in Sendai virus (SV)-treated human endometrial adenocarcinoma HEC1B cells. DNA-PK-dependent phosphorylation at Thr-135 is thought to retain transcriptionally active IRF-3 in the nucleus (Karpova AY et al. 2002). | |||
| REACT_163740 (Reactome) | DHX36 senses CpG-A in cytosol of human plasmacytoid dendritic cells. DEAH domain of DHX36 was found to be essential for binding CpG-A [Kim T et al 2010]. | |||
| REACT_163749 (Reactome) | E3 ubiquitin-protein ligase TRIM32 and TRIM56 were shown to enhance type I IFN induction and cellular antiviral response by promoting K63-linked ubiquitination of STING. | |||
| REACT_163766 (Reactome) | TBK1 phosphorylates STAT6 on Ser407, which in turn activates another unidentified tyrosine kinase to phosphorylate STAT6 on Tyr641. Mutant constructs with Tyr641 replaced by Phe totally abolished STAT6 activity in response to virus or IL-4/IL-13 (Chen H et al. 2011). | |||
| REACT_163771 (Reactome) | DHX9 binds CpG-B in human plasmacytoid dendritic cells (pDC). The DUF domain of DHX9 was shown to be essential for binding CpG-B [Kim T et al 2010]. | |||
| REACT_163772 (Reactome) | DNA damage sensor, meiotic recombination 11 homolog A (MRE11) has been shown to function as a cytosolic sensor of dsDNA. Cells with a mutation of MRE11 gene derived from a patient with ataxia-telangiectasia-like disorder, and cells in which Mre11 was knocked down, had defects in dsDNA-induced type I IFN production (Kondo T et al. 2013) | |||
| REACT_163774 (Reactome) | Beta-catenin undergoes phosphorylation at Ser552 in a Lrrfip1-dependent manner in pathogen-infected mouse macrophages (Yang P et al. 2010). Studies on human cells showed that the protein kinase Akt can phosphorylate beta-catenin at Ser552 upon treatment with various stimuli such as epidermal growth factor (EGF) or hepatitis C virus (HCV). However, it remains to be determined which kinase is involved in up-regulation of beta-catenin downstream of LRRFIP1 (Fang D et al. 2007; Bose SK et al. 2012). Phosphorylated beta-catenin translocates to the nucleus. | |||
| REACT_163779 (Reactome) | Cyclic dinucleotides (such as c-di-GMP and c-di-AMP) are signaling molecules produced by bacteria. In host cells they are recognized by DNA sensors such as DDX41 and STING to trigger IFN production in a STING-dependent manner (Burdette DL et al. 2011; Yin Q et al. 2012; Parvatiyar K et al. 2012). Cyclic adenosine monophosphate-guanosine monophosphate (cyclic GMP-AMP, cGAMP) has been also implicated in stimulating host responses via STING (Wu J et al. 2013). Chemically synthesized cGAMP was shown to induce IFN-beta production in mouse fibrosarcoma cell line L929 with much higher potency than c-di-GMP and c-di-AMP. Most importantly, cGAMP was identified as the first cyclic di-nucleotide produced by mammalian cells (Wu J et al. 2013). DNA transfection or DNA virus infection of human and mouse cells triggered production of the endogenous second messenger cGAMP, which in turn interacted with STING to activate dimerization of IRF3 and induction of IFN beta (Wu J et al. 2013). cGAMP synthase (cGAS) was reported to catalyze the cGAMP production in the presence of DNA (Sun L et al. 2013). The structural study showed that cGAMP generated by cGAS contains G(2',5')pA and A(3',5')pG phosphodiester linkages, which is distinct from bacterial 3',5' cyclic dinucleotides (Gao P et al. 2013). | |||
| REACT_163797 (Reactome) | Tripartite motif (TRIM) family member TRIM56 was shown to interact with STING upon DNA stimulation promoting lysine 63-linked ubiquitination of STING and type I IFN induction (Tsuchida T et al. 2010). Another member of the family TRIM32 has also been implicated in K63-linked ubiquitination of STING (Zhang J et al. 2012). | |||
| REACT_163821 (Reactome) | The cytosolic protein beta-catenin is known as a transcriptional cofactor in Wnt signaling pathway. Beta-catenin has been also implicated in LRRFIP1-mediated induction of type I IFN. Beta-catenin was shown to bind Lrrfip1 in L. monocytogenes-infected mouse macrophages but not in resting macrophages (Yang P et al 2010). The interaction of beta-catenin and LRRFIP1 was also reported for human proteins when they were co-expressed in human embryonic kidney 293T (HEK293T) cells followed by co-immunoprecipitation assay. The co-immunoprecipitation results were consistent with the GST-pulldown data (Lee YH and Stallcup MR 2006). | |||
| REACT_163840 (Reactome) | Phosphorylated beta-catenin migrates to the nucleus where it functions as a coactivator of IRF3-dependent transcription (Yang P et al. 2010). Beta-catenin transport to the nucleus is thought to occur in a NLS (nuclear localization signal)- and importin-independent manner through direct interaction with the nuclear pore complex (NPC) components. This has been shown to be the case for Wnt-signaling in mammalian cells (Yokoya F et al. 1999; Koike M et al. 2004; Sharma M et al. 2012) | |||
| REACT_163856 (Reactome) | NLRP4 regulate the host immune responses by recruiting E3 ubiquitin-protein ligase DTX4 to the kinase TBK1. DTX4 promotes K48-linked ubiquitination of TBK1 resulting in the degradation of TBK1 and downregulation of IFN signaling (Cui J et al. 2012). | |||
| REACT_163868 (Reactome) | Direct binding assays with radiolabeled substrate showed that the association of STING protein (residues 139-379) with [32P]-cGAMP was inhibited in the presence of competing cold cGAMP, c-di-GMP or c-di-AMP, suggesting that the cGAMP binding sites on STING might overlap with those that interact with c-di-GMP and c-di-AMP (Wu J et al.2013). Indeed, mutations of several residues that were shown to participate in the binding of STING to c-di-GMP, including S161Y, Y240S and N242A, also impaired the binding of STING to cGAMP (Yin Q et al. 2012; Wu J et al.2013). Structural study revealed that cGAMP generated by cGAS contains G(2',5')pA and A(3',5')pG phosphodiester linkages, which is distinct from bacterial 3',5' cyclic dinucleotides (Gao P et al. 2013). | |||
| REACT_163891 (Reactome) | Following tyrosine phosphorylation and dimerization STAT6 translocates to the nucleus to initiate the transcription. Virus-induced STAT6 was shown to up-regulate expression of the specific gene set (Chen H et al. 2011). Among the targets are chemokines CCL2, CCL20, and CCL26, which attract cells of immune system to fight the infection. | |||
| REACT_163897 (Reactome) | RNA polymerase III (POL III) was reported to sense and transcribe cytosolic AT-rich dsDNA into 5'-triphosphate poly(A-U) RNA in human and mouse cells. This dsRNA ligand in turn activated retinoic acid-inducible gene I (RIG-I) leading to production of type I interferon and activation of the transcription factor NF-kappaB (Chiu YH et al. 2009, Ablasser A et al. 2009). Knockdown of POL III expression by siRNA or inhibition of its enzymatic activity by specific chemical inhibitor ML-60218 prevented IFN beta induction in HEK293 cells stimulated with DNA viruses or poly(dA-dT) (Chiu YH et al. 2009, Ablasser A et al. 2009). Moreover, Pol-III inhibition blocked interferon induction by intracellular Legionella pneumophila bacteria [Chiu YH et al 2009]. This project represents cytosolic RNA polymerase III as a complex comprising 17 subunits, although the precise biochemical composition of the cytosolic holoenzyme complex which specifically recognizes AT-rich DNA is not yet known. | |||
| REACT_163902 (Reactome) | Beta-catenin increases IFN-beta expression by binding to the C-terminal domain of the transcription factor IRF3 and recruiting the acetyltransferase p300 to the IFN-beta enhanceosome via IRF3. | |||
| REACT_163915 (Reactome) | LRRFIP1 can recognize both AT-rich B-form dsDNA and GC-rich Z-form dsDNA (Yang P et al. 2010). LRRFIP1 contains three domains, an N-terminal helical region of unknown function, a central coiled coil (CC) domain that interacts with protein flightless I homolog (FLII), and a C-terminal DNA binding or nucleic acid recognition domain (DBD). The structural and biophysical studies revealed that the CC-domain of LRRFIP1 forms stable homodimer in solution while the CC-DBD construct was found to be an oligomer suggesting that the full length LRRFIP1 may also form dimers or larger oligomers upon DNA binding (Nguyen JB and Modis Y 2012). | |||
| REACT_163955 (Reactome) | Upon viral infection STAT6 undergoes Ser407 phosphorylation, which was shown to depend on the TBK1 kinase activity, but not on the kinase JAK, which phosphorylates STAT6 on Tyr641 in IL4-mediated signaling (Chen H et al. 2011). | |||
| REACT_163957 (Reactome) | TREX1 digests unpaired nucleotides on ssDNA and dsDNA ends through a 3' to 5' exonuclease activity (Perrino FW et al. 1994; de Silva U et al. 2007; Lehtinen DA et al. 2008; Fye JM et al 2011). Upon viral infection the TREX1-deficient human and mouse cells were found to be more resistant to different types of RNA viruses, suggesting that TREX1 activity may inhibit the host innate immune responses by clearing viral DNA generated during reverse transcription (Yan N et al. 2010; Hasan M et al. 2012). | |||
| REACT_163991 (Reactome) | Both DHX36 and DHX9 were found to interact with MyD88 when co-expressed in human embryonic kidney 293T cells. Moreover, the HA2 and DUF domains of DHX were critical for interaction with the TIR domain of MyD88 [Kim T et al 2010]. DHX9 or DHX36 knockdown by siRNA inhibited cytokine release in human GEN2.2 cell line (leukemic pDC cells) in response to CpG-ODN or to HSV but not to RNA viruses. Furthermore, knockdown of DHX36 diminished the nuclear localization of IRF7 in CpG-A-stimulated cells, while knockdown of DHX9 inhibited nuclear localization of NF-kappaB p50 in response to CpG-B. Thus, DHX36 and DHX9 are thought to trigger MyD88-dependent IRF7 and NF-kappaB activation respectively [Kim T et al 2010]. | |||
| REACT_24920 (Reactome) | p-IRF7 dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes. | |||
| REACT_6848 (Reactome) | In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits. A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB. | |||
| REACT_6906 (Reactome) | NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NFkappa-B2), All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefor, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes. | |||
| REACT_6973 (Reactome) |
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| RIPK1 | REACT_118851 (Reactome) | |||
| RIPK3 | REACT_118851 (Reactome) | |||
| RNA Polymerase III Holoenzyme | mim-catalysis | REACT_163897 (Reactome) | ||
| STAT6 | REACT_163667 (Reactome) | |||
| STING activators | Arrow | REACT_147703 (Reactome) | ||
| STING:STING | Arrow | REACT_163630 (Reactome) | ||
| STING:STING | REACT_147703 (Reactome) | |||
| STING:STING | REACT_147763 (Reactome) | |||
| STING:STING | REACT_163667 (Reactome) | |||
| STING:STING | REACT_163868 (Reactome) | |||
| STING:TBK1:IRF3 | Arrow | REACT_147703 (Reactome) | ||
| STING:TBK1:IRF3 | REACT_147901 (Reactome) | |||
| STING:TBK1:STAT6 | Arrow | REACT_163667 (Reactome) | ||
| STING:TBK1:STAT6 | REACT_163707 (Reactome) | |||
| STING:TRIM32/TRIM56 | Arrow | REACT_163797 (Reactome) | ||
| STING:TRIM32/TRIM56 | REACT_163749 (Reactome) | |||
| STING:TRIM32/TRIM56 | mim-catalysis | REACT_163749 (Reactome) | ||
| STING:c-di-GMP | Arrow | REACT_147763 (Reactome) | ||
| STING:cGAMP | Arrow | REACT_163868 (Reactome) | ||
| STING:p-S172-TBK1:IRF3 | Arrow | REACT_147901 (Reactome) | ||
| STING:p-S172-TBK1:IRF3 | REACT_147769 (Reactome) | |||
| STING:p-S172-TBK1:IRF3 | mim-catalysis | REACT_147769 (Reactome) | ||
| STING:p-S172-TBK1:STAT6 | Arrow | REACT_163707 (Reactome) | ||
| STING:p-S172-TBK1:STAT6 | REACT_163955 (Reactome) | |||
| STING:p-S172-TBK1:STAT6 | mim-catalysis | REACT_163955 (Reactome) | ||
| STING:p-S172-TBK1 | Arrow | REACT_147769 (Reactome) | ||
| STING:p-S172-TBK1 | Arrow | REACT_163955 (Reactome) | ||
| TBK1 | REACT_118783 (Reactome) | |||
| TBK1 | REACT_147703 (Reactome) | |||
| TBK1 | REACT_163667 (Reactome) | |||
| TMEM173 | REACT_163630 (Reactome) | |||
| TMEM173 | REACT_163797 (Reactome) | |||
| TMP | Arrow | REACT_163957 (Reactome) | ||
| TREX1 dimer | Arrow | REACT_163957 (Reactome) | ||
| TREX1 dimer | REACT_163654 (Reactome) | |||
| TREX1 dimer | TBar | REACT_147703 (Reactome) | ||
| TREX1:viral DNA | Arrow | REACT_163654 (Reactome) | ||
| TREX1:viral DNA | REACT_163957 (Reactome) | |||
| TREX1:viral DNA | mim-catalysis | REACT_163957 (Reactome) | ||
| TRIM21 | REACT_163639 (Reactome) | |||
| TRIM21 | TBar | REACT_163653 (Reactome) | ||
| TRIM21 | mim-catalysis | REACT_163639 (Reactome) | ||
| TRIM32/TRIM56 | Arrow | REACT_163749 (Reactome) | ||
| TRIM32/TRIM56 | REACT_163797 (Reactome) | |||
| Ub | REACT_163639 (Reactome) | |||
| Ub | REACT_163749 (Reactome) | |||
| Ub | REACT_163856 (Reactome) | |||
| Unmethylated CpG DNA | REACT_163740 (Reactome) | |||
| Unmethylated CpG DNA | REACT_163771 (Reactome) | |||
| ZBP1 | REACT_118621 (Reactome) | |||
| beta-catenin:IRF3:p300 | Arrow | REACT_163902 (Reactome) | ||
| c-GMP-AMP | Arrow | REACT_163779 (Reactome) | ||
| c-GMP-AMP | REACT_163868 (Reactome) | |||
| c-di-GMP | REACT_147763 (Reactome) | |||
| cGAS ligand | REACT_163636 (Reactome) | |||
| cGAS:dsDNA | Arrow | REACT_163636 (Reactome) | ||
| cGAS:dsDNA | mim-catalysis | REACT_163779 (Reactome) | ||
| dAMP | Arrow | REACT_163957 (Reactome) | ||
| dCMP | Arrow | REACT_163957 (Reactome) | ||
| dGMP | Arrow | REACT_163957 (Reactome) | ||
| dsDNA:IFI16 | Arrow | REACT_147878 (Reactome) | ||
| dsDNA:LRR
FLII-interacting protein 1dimer | Arrow | REACT_163774 (Reactome) | ||
| dsDNA:LRR
FLII-interacting protein 1dimer | Arrow | REACT_163915 (Reactome) | ||
| dsDNA:LRR
FLII-interacting protein 1dimer | REACT_163821 (Reactome) | |||
| dsDNA:LRRFIP1:beta-catenin | Arrow | REACT_163821 (Reactome) | ||
| dsDNA:LRRFIP1:beta-catenin | REACT_163774 (Reactome) | |||
| dsDNA:ZBP1:RIP1:RIP3 | Arrow | REACT_118851 (Reactome) | ||
| dsDNA:ZBP1:RIP1:RIP3 | Arrow | REACT_6973 (Reactome) | ||
| dsDNA:ZBP1:pS-172-TBK1 | Arrow | REACT_118685 (Reactome) | ||
| dsDNA:ZBP1:pS-172-TBK1 | Arrow | REACT_118783 (Reactome) | ||
| dsDNA:ZBP1:pS-172-TBK1 | REACT_118613 (Reactome) | |||
| dsDNA:ZBP1:pS-172-TBK:IRF3 | Arrow | REACT_118613 (Reactome) | ||
| dsDNA:ZBP1:pS-172-TBK:IRF3 | REACT_118685 (Reactome) | |||
| dsDNA:ZBP1 | Arrow | REACT_118621 (Reactome) | ||
| dsDNA:ZBP1 | REACT_118783 (Reactome) | |||
| dsDNA:ZBP1 | REACT_118851 (Reactome) | |||
| microbial dsDNA | REACT_118621 (Reactome) | |||
| microbial dsDNA | REACT_163719 (Reactome) | |||
| microbial dsDNA | REACT_163915 (Reactome) | |||
| p-2S-IRF7:p-2S-IRF7 | Arrow | REACT_24920 (Reactome) | ||
| p-2S-IRF7:p-2S-IRF7 | REACT_24920 (Reactome) | |||
| p-4S,T404-IRF3 | Arrow | REACT_118685 (Reactome) | ||
| p-4S,T404-IRF3 | Arrow | REACT_147769 (Reactome) | ||
| p-4S,T404-IRF3 | REACT_147821 (Reactome) | |||
| p-S172,K48polyUb-TBK1 complexes | Arrow | REACT_163856 (Reactome) | ||
| p-S172-TBK1 complexes | REACT_163683 (Reactome) | |||
| p-S407,Y641-STAT6 dimer | Arrow | REACT_163668 (Reactome) | ||
| p-S407,Y641-STAT6 dimer | Arrow | REACT_163891 (Reactome) | ||
| p-S407,Y641-STAT6 dimer | REACT_163891 (Reactome) | |||
| p-S407,Y641-STAT6 | Arrow | REACT_163766 (Reactome) | ||
| p-S407,Y641-STAT6 | REACT_163668 (Reactome) | |||
| p-S407-STAT6 | Arrow | REACT_163955 (Reactome) | ||
| p-S407-STAT6 | REACT_163766 (Reactome) | |||
| p-S552-CTNNB1 | Arrow | REACT_163774 (Reactome) | ||
| p-S552-CTNNB1 | Arrow | REACT_163840 (Reactome) | ||
| p-S552-CTNNB1 | REACT_163840 (Reactome) | |||
| p-S552-CTNNB1 | REACT_163902 (Reactome) | |||
| p-T,4S-IRF3:p-T,4S-IRF3 | Arrow | REACT_118567 (Reactome) | ||
| p-T,4S-IRF3:p-T,4S-IRF3 | Arrow | REACT_147821 (Reactome) | ||
| p-T,4S-IRF3:p-T,4S-IRF3 | REACT_118567 (Reactome) | |||
| p-T,4S-IRF3:p-T,4S-IRF3 | REACT_163902 (Reactome) | |||
| viral dsRNA:TLR3:TRIF:RIP1 | Arrow | REACT_6973 (Reactome) | ||
| viral DNA with 3' sticky ends | REACT_163654 (Reactome) | |||
| viral dsDNA | REACT_147878 (Reactome) |
