Type I interferons (IFNs) are composed of various genes including IFN alpha (IFNA), beta (IFNB), omega, epsilon, and kappa. In humans the IFNA genes are composed of more than 13 subfamily genes, whereas there is only one IFNB gene. The large family of IFNA/B proteins all bind to a single receptor which is composed of two distinct chains: IFNAR1 and IFNAR2. The IFNA/B stimulation of the IFNA receptor complex leads to the formation of two transcriptional activator complexes: IFNA-activated-factor (AAF), which is a homodimer of STAT1 and IFN-stimulated gene factor 3 (ISGF3), which comprises STAT1, STAT2 and a member of the IRF family, IRF9/P48. AAF mediates activation of the IRF-1 gene by binding to GAS (IFNG-activated site), whereas ISGF3 activates several IFN-inducible genes including IRF3 and IRF7.
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Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J.; ''Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase.''; PubMedEurope PMCScholia
Leaman DW, Chawla-Sarkar M, Vyas K, Reheman M, Tamai K, Toji S, Borden EC.; ''Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis.''; PubMedEurope PMCScholia
Yan H, Krishnan K, Greenlund AC, Gupta S, Lim JT, Schreiber RD, Schindler CW, Krolewski JJ.; ''Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein.''; PubMedEurope PMCScholia
Rani MR, Leaman DW, Han Y, Leung S, Croze E, Fish EN, Wolfman A, Ransohoff RM.; ''Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase.''; PubMedEurope PMCScholia
Andersson I, Bladh L, Mousavi-Jazi M, Magnusson KE, Lundkvist A, Haller O, Mirazimi A.; ''Human MxA protein inhibits the replication of Crimean-Congo hemorrhagic fever virus.''; PubMedEurope PMCScholia
Li X, Leung S, Qureshi S, Darnell JE, Stark GR.; ''Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha.''; PubMedEurope PMCScholia
Clark JD, Flanagan ME, Telliez JB.; ''Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.''; PubMedEurope PMCScholia
Geiger TR, Martin JM.; ''The Epstein-Barr virus-encoded LMP-1 oncoprotein negatively affects Tyk2 phosphorylation and interferon signaling in human B cells.''; PubMedEurope PMCScholia
Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, Richardson P.; ''COVID-19: combining antiviral and anti-inflammatory treatments.''; PubMedEurope PMCScholia
Chuntharapai A, Gibbs V, Lu J, Ow A, Marsters S, Ashkenazi A, De Vos A, Jin Kim K.; ''Determination of residues involved in ligand binding and signal transmission in the human IFN-alpha receptor 2.''; PubMedEurope PMCScholia
Martinand C, Montavon C, Salehzada T, Silhol M, Lebleu B, Bisbal C.; ''RNase L inhibitor is induced during human immunodeficiency virus type 1 infection and down regulates the 2-5A/RNase L pathway in human T cells.''; PubMedEurope PMCScholia
Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.; ''Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.''; PubMedEurope PMCScholia
Improta T, Schindler C, Horvath CM, Kerr IM, Stark GR, Darnell JE.; ''Transcription factor ISGF-3 formation requires phosphorylated Stat91 protein, but Stat113 protein is phosphorylated independently of Stat91 protein.''; PubMedEurope PMCScholia
Der SD, Yang YL, Weissmann C, Williams BR.; ''A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis.''; PubMedEurope PMCScholia
Le Roy F, Bisbal C, Silhol M, Martinand C, Lebleu B, Salehzada T.; ''The 2-5A/RNase L/RNase L inhibitor (RLI) [correction of (RNI)] pathway regulates mitochondrial mRNAs stability in interferon alpha-treated H9 cells.''; PubMedEurope PMCScholia
Kohli A, Zhang X, Yang J, Russell RS, Donnelly RP, Sheikh F, Sherman A, Young H, Imamichi T, Lempicki RA, Masur H, Kottilil S.; ''Distinct and overlapping genomic profiles and antiviral effects of Interferon-λ and -α on HCV-infected and noninfected hepatoma cells.''; PubMedEurope PMCScholia
Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM.; ''Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways.''; PubMedEurope PMCScholia
Malakhova OA, Kim KI, Luo JK, Zou W, Kumar KG, Fuchs SY, Shuai K, Zhang DE.; ''UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity.''; PubMedEurope PMCScholia
Roisman LC, Jaitin DA, Baker DP, Schreiber G.; ''Mutational analysis of the IFNAR1 binding site on IFNalpha2 reveals the architecture of a weak ligand-receptor binding-site.''; PubMedEurope PMCScholia
Der SD, Zhou A, Williams BR, Silverman RH.; ''Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.''; PubMedEurope PMCScholia
Nyman TA, Tölö H, Parkkinen J, Kalkkinen N.; ''Identification of nine interferon-alpha subtypes produced by Sendai virus-induced human peripheral blood leucocytes.''; PubMedEurope PMCScholia
Qureshi SA, Salditt-Georgieff M, Darnell JE.; ''Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3.''; PubMedEurope PMCScholia
Chill JH, Quadt SR, Levy R, Schreiber G, Anglister J.; ''The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding.''; PubMedEurope PMCScholia
de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BR.; ''Functional classification of interferon-stimulated genes identified using microarrays.''; PubMedEurope PMCScholia
Morrison BH, Bauer JA, Kalvakolanu DV, Lindner DJ.; ''Inositol hexakisphosphate kinase 2 mediates growth suppressive and apoptotic effects of interferon-beta in ovarian carcinoma cells.''; PubMedEurope PMCScholia
Chawla-Sarkar M, Lindner DJ, Liu YF, Williams BR, Sen GC, Silverman RH, Borden EC.; ''Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis.''; PubMedEurope PMCScholia
Sadler AJ, Williams BR.; ''Interferon-inducible antiviral effectors.''; PubMedEurope PMCScholia
Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, Rawling M, Savory E, Stebbing J.; ''Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.''; PubMedEurope PMCScholia
Müller M, Briscoe J, Laxton C, Guschin D, Ziemiecki A, Silvennoinen O, Harpur AG, Barbieri G, Witthuhn BA, Schindler C.; ''The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction.''; PubMedEurope PMCScholia
Domanski P, Fish E, Nadeau OW, Witte M, Platanias LC, Yan H, Krolewski J, Pitha P, Colamonici OR.; ''A region of the beta subunit of the interferon alpha receptor different from box 1 interacts with Jak1 and is sufficient to activate the Jak-Stat pathway and induce an antiviral state.''; PubMedEurope PMCScholia
Martinez-Moczygemba M, Gutch MJ, French DL, Reich NC.; ''Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3.''; PubMedEurope PMCScholia
Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, Favata MF, Wen X, Shi J, McGee R, Haley PJ, Shepard S, Rodgers JD, Yeleswaram S, Hollis G, Newton RC, Metcalf B, Friedman SM, Vaddi K.; ''Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050.''; PubMedEurope PMCScholia
Wreschner DH, McCauley JW, Skehel JJ, Kerr IM.; ''Interferon action--sequence specificity of the ppp(A2'p)nA-dependent ribonuclease.''; PubMedEurope PMCScholia
Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK.; ''TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B.''; PubMedEurope PMCScholia
You M, Yu DH, Feng GS.; ''Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway.''; PubMedEurope PMCScholia
Martinand C, Salehzada T, Silhol M, Lebleu B, Bisbal C.; ''RNase L inhibitor (RLI) antisense constructions block partially the down regulation of the 2-5A/RNase L pathway in encephalomyocarditis-virus-(EMCV)-infected cells.''; PubMedEurope PMCScholia
Gavutis M, Lata S, Lamken P, Müller P, Piehler J.; ''Lateral ligand-receptor interactions on membranes probed by simultaneous fluorescence-interference detection.''; PubMedEurope PMCScholia
Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE.; ''Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions.''; PubMedEurope PMCScholia
Leaman DW, Chawla-Sarkar M, Jacobs B, Vyas K, Sun Y, Ozdemir A, Yi T, Williams BR, Borden EC.; ''Novel growth and death related interferon-stimulated genes (ISGs) in melanoma: greater potency of IFN-beta compared with IFN-alpha2.''; PubMedEurope PMCScholia
Pervolaraki K, Rastgou Talemi S, Albrecht D, Bormann F, Bamford C, Mendoza JL, Garcia KC, McLauchlan J, Höfer T, Stanifer ML, Boulant S.; ''Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance.''; PubMedEurope PMCScholia
Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen X, Li Y, Waeltz P, Rupar M, Burn T, Lo Y, Kelley J, Covington M, Shepard S, Rodgers JD, Haley P, Kantarjian H, Fridman JS, Verstovsek S.; ''Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms.''; PubMedEurope PMCScholia
Cao XM, Guy GR, Sukhatme VP, Tan YH.; ''Regulation of the Egr-1 gene by tumor necrosis factor and interferons in primary human fibroblasts.''; PubMedEurope PMCScholia
Xu D, Qu CK.; ''Protein tyrosine phosphatases in the JAK/STAT pathway.''; PubMedEurope PMCScholia
Li X, Leung S, Kerr IM, Stark GR.; ''Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling.''; PubMedEurope PMCScholia
Friedman RL, Manly SP, McMahon M, Kerr IM, Stark GR.; ''Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells.''; PubMedEurope PMCScholia
Gauzzi MC, Velazquez L, McKendry R, Mogensen KE, Fellous M, Pellegrini S.; ''Interferon-alpha-dependent activation of Tyk2 requires phosphorylation of positive regulatory tyrosines by another kinase.''; PubMedEurope PMCScholia
Justesen J, Hartmann R, Kjeldgaard NO.; ''Gene structure and function of the 2'-5'-oligoadenylate synthetase family.''; PubMedEurope PMCScholia
Lamken P, Lata S, Gavutis M, Piehler J.; ''Ligand-induced assembling of the type I interferon receptor on supported lipid bilayers.''; PubMedEurope PMCScholia
Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T.; ''Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1.''; PubMedEurope PMCScholia
Effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). These ISGs are mainly implicated in anti-viral, anti-angiogenic, immunomodulatory, cell cycle inhibitory effects and apoptotic functions. All IFNA/B-stimulated genes have a conserved region of about 15bp in their promoter called the Interferon Stimulation Response Element (ISRE). The transcription factor ISGF3 binds to this ISRE and induce the transcription of these genes by IFN.
Around 300 IFN-induced genes have been identified from different oligonucleotide microarray studies in melanoma (WM9) and fibrosarcoma (HT1080) cell lines as well as from human dendritic cells treated with IFN. Only the proteins which are well studied and their function characterized are represented here.
2-5A-dependent ribonuclease (RNASEL) is an endoribonuclease that is activated in the interferon (IFN) antiviral response. Its anti-viral effects are probably a combination of induction of apoptosis, cleavage of viral mRNA and induction of other anti-viral genes. ATP-binding cassette sub-family E member 1 (ABCE1, aka RNase L inhibitor, RLI) directly interacts with RNASEL and inhibits its endoribonuclease activity, thus antagonising the anti-viral effect of the IFN-regulated 2-5A/RNase L pathway (Martinand et al. 1998, Martinand et al. 1999, Le Roy et al. 2001).
Under certain conditions type I IFNs, IFNA/B are able to activate genes through a second STAT-based signaling cascade enabling the formation of p-STAT1:p-STAT1 homodimers called IFNA-activated-factor (AAF).
Phosphorylated tyrosine residue 466 on IFNAR1 acts as a docking site for STAT2. Latent STAT2 is recruited to this phosphotyrosine residue via its SH2 domain.
The ligand IFNalpha/beta (IFNA/B), interacts independently with the two interferon receptor subunits. Based on detailed binding studies with the extracellular domains of the receptor subunits tethered onto solid-supported membranes, a two-step binding mechanism was experimentally confirmed, where the ligand binds first to one of the receptor subunits and then recruits the second subunit (Gavutis et al. 2005). The efficiency of recruitment of the IFNA receptor subunits by the IFN ligand depends on the absolute and relative concentration of the receptor subunits. IFNAR2 chain constitutively associates with JAK1 kinase in its cytoplasmic domain. In addition IFNAR2 also binds STAT2 in a constitutive manner and this interaction is biochemically different from the interaction of STAT2 with phosphorylated IFNAR1. Although this interaction facilitates the recruitment of STAT2 to the receptors, the biological significance of this constitutive STAT2 interaction to IFNAR2 remains unclear (Nguyen et al, 2002). IFNAR2 not only associates with STAT2, but also with STAT1 and this binding of STAT1 to IFNAR2 depends on the presence of STAT2 but not vice versa. IFNA/B may first bind to the high-affinity subunit IFNAR2 and subsequently recruit IFNAR1 in a transient fashion (Lamken et al. 2004). Different type I IFNs interact differently with the two IFNA receptor (IFNAR) subunits, IFNB generates a more stable signaling complex than IFNA subtypes. The interaction between IFNalpha2 (IFNA2) and IFNAR2 has an affinity in the nM range, whereas the affinity of the interaction with INFB is about tenfold tighter.
The resultant ISGF3 trimeric complex then migrates to the nucleus and binds to interferon-stimulated response elements (ISREs). IRF9 is the DNA binding part of this ISGF3 complex. These ISREs are present in the promoters of a subset of ISGs (interferon stimulated genes), such as promyelocytic leukemia (PML), ISG15 ubiquitin-like modifier (ISG15), interferon-induced protein with tetratricopeptide repeats 2 (ISG54) and interferon alpha-inducible protein 6 (IFI6) to elicit an antiviral response.
The extracellular domain of IFNAR1 is atypical, consisting of a tandem array of four FNIII domains and the first three N-terminal FNIII domains are involved in ligand recognition. IFNAR1 is recruited to the binary complex (IFNA/B:IFNAR2) on the membrane to form the ternary complex (IFNAR2:IFNA/B:IFNAR1). TYK2 kinase is pre-associated with IFNAR1 and JAK1 with IFNAR2. The binding of IFNA/B to IFNA receptors brings these JAK kinase together, allowing cross-phosphorylation and kinase activation.
The phosphorylated STAT2:STAT1 heterodimer associates with interferon-regulating factor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex.
Phosphotyrosine on STAT2 acts as docking site for STAT1 molecules. STAT1 binds to phosphorylated STAT2 and this is followed by STAT1 phosphorylation on tyrosine residue 701 (Y701). These STATs recruited to the phosporylated IFNAR1 form two distinct transcriptional activator complexes, namely, IFN-alpha-activated factor (AAF) and IFN-stimulated gene factor 3 (ISGF3). AAF is a homodimer of STAT1, whereas ISGF3 is a heterotrimeric complex of STAT1, STAT2 and IRF9 (also known as p48 or ISGF3gamma) (Honda et al. 2005).
The two chains IFNAR1 and IFNAR2 are pre-associated with the JAK kinases TYK2 and JAK1, respectively. Receptor heterodimerization brings these JAK kinases into close proximity and they are activated by reciprocal trans-phosphorylation. Tyr-1054 and Tyr-1055 within the activation loop of TYK2 sub-domain VII are critical for TYK2 activation. For JAK1 two tyrosine residues with in the KEYY motif (Tyr 1034 and Tyr 1035) of the kinase domain are thought to be transphosphorylated.
TYK2 functions as part of a receptor complex to trigger intracellular signaling in response to IFNA/B. TYK2 bound to IFNAR1 subunit is activated in response to IFNA/B treatment and this in turn phosphorylates two tyrosine residues Y466 and Y481 in the juxta-membrane region of IFNAR1.
STAT2 recruited to the IFNAR1 subunit then becomes tyrosine phosphorylated on residue 690 by TYK2 kinase. This phosphotyrosine provides a docking site for recruitment of STAT1 to IFNAR1, which is then tyrosine phosphorylated and activated.
SOCS1/3 are the major negative regulators of IFNA/B signaling. They inhibit JAKs catalytic activity directly through their kinase inhibitory region (KIR) and turn off downstream IFNA/B signaling. SOCS1 may also prevent IFN signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway.
UBP43, a type I IFN-inducible cysteine protease acts as a negative regulator of type I IFN signaling. UBP43 binds directly to IFNAR2 and blocks JAK-receptor interaction leading to inhibition of downstream phosphorylation and other signaling events.
IFNA-activated-factor (AAF) translocates to nucleus and then promotes the expression of a distinct set of gamma activated sequence (GAS)-driven genes like IRF1. IRF1, in turn, induces the transcription of ISG15, ISG54 and IFI6 genes. This second pathway of STAT1 homodimer formation is primarily activated by IFNG and is likely to account for some of the functional overlap between type I and type II IFNs.
Non-receptor tyrosine-protein kinase TYK2 binds and is inhibited by several small molecule drugs (Clark et al. 2014, Gibbons et al. 2012). TYK2 is related to the Janus kinases (JAKs) family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. Drugs that inhibit these kinases are thus plausible candidates for treatment of severe host inflammatory reactions to viral infection (Richardson et al. 2020, Stebbing et al. 2020).
The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. JAK1 binds to and is inhibited by several small molecule drugs (Clark et al. 2014, Fridman et al. 2010). Drugs that inhibit these kinases such as baricitinib, tofacitinib and ruxolitinib are thus plausible candidates for treatment of severe host inflammatory reactions to viral infection (Peterson et al. 2020, Richardson et al. 2020).
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genes with ISRE
promoter elementsAnnotated Interactions
IFNAR2 chain constitutively associates with JAK1 kinase in its cytoplasmic domain. In addition IFNAR2 also binds STAT2 in a constitutive manner and this interaction is biochemically different from the interaction of STAT2 with phosphorylated IFNAR1. Although this interaction facilitates the recruitment of STAT2 to the receptors, the biological significance of this constitutive STAT2 interaction to IFNAR2 remains unclear (Nguyen et al, 2002). IFNAR2 not only associates with STAT2, but also with STAT1 and this binding of STAT1 to IFNAR2 depends on the presence of STAT2 but not vice versa.
IFNA/B may first bind to the high-affinity subunit IFNAR2 and subsequently recruit IFNAR1 in a transient fashion (Lamken et al. 2004). Different type I IFNs interact differently with the two IFNA receptor (IFNAR) subunits, IFNB generates a more stable signaling complex than IFNA subtypes. The interaction between IFNalpha2 (IFNA2) and IFNAR2 has an affinity in the nM range, whereas the affinity of the interaction with INFB is about tenfold tighter.
genes with ISRE
promoter elementsgenes with ISRE
promoter elements