ISG15 antiviral mechanism (Homo sapiens)
From WikiPathways
Description
Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1169408
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- Takeuchi T, Yokosawa H.; ''ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity.''; PubMed Europe PMC Scholia
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- Zou W, Papov V, Malakhova O, Kim KI, Dao C, Li J, Zhang DE.; ''ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form thioester bond with ubiquitin.''; PubMed Europe PMC Scholia
- Takeuchi T, Kobayashi T, Tamura S, Yokosawa H.; ''Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation.''; PubMed Europe PMC Scholia
- Takeuchi T, Iwahara S, Saeki Y, Sasajima H, Yokosawa H.; ''Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE.; ''UBP43 (USP18) specifically removes ISG15 from conjugated proteins.''; PubMed Europe PMC Scholia
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- Wong JJ, Pung YF, Sze NS, Chin KC.; ''HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets.''; PubMed Europe PMC Scholia
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- Gottwein E, Jäger S, Habermann A, Kräusslich HG.; ''Cumulative mutations of ubiquitin acceptor sites in human immunodeficiency virus type 1 gag cause a late budding defect.''; PubMed Europe PMC Scholia
- Tsuchida T, Kawai T, Akira S.; ''Inhibition of IRF3-dependent antiviral responses by cellular and viral proteins.''; PubMed Europe PMC Scholia
- Zou W, Zhang DE.; ''The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligase.''; PubMed Europe PMC Scholia
- Durfee LA, Kelley ML, Huibregtse JM.; ''The basis for selective E1-E2 interactions in the ISG15 conjugation system.''; PubMed Europe PMC Scholia
- Yuan W, Krug RM.; ''Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein.''; PubMed Europe PMC Scholia
- Okumura A, Pitha PM, Harty RN.; ''ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity.''; PubMed Europe PMC Scholia
- Tang Y, Zhong G, Zhu L, Liu X, Shan Y, Feng H, Bu Z, Chen H, Wang C.; ''Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1 protein.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| AMP | Arrow | REACT_115543 (Reactome)  | ||
| AMP | Arrow | REACT_115658 (Reactome) | ||
| AMP | Arrow | REACT_115843 (Reactome) | ||
| AMP | Arrow | REACT_115890 (Reactome) | ||
| AMP | Arrow | REACT_115934 (Reactome) | ||
| AMP | Arrow | REACT_115965 (Reactome) | ||
| AMP | Arrow | REACT_116132 (Reactome) | ||
| ATP | REACT_115543 (Reactome) | |||
| ATP | REACT_115658 (Reactome) | |||
| ATP | REACT_115843 (Reactome) | |||
| ATP | REACT_115890 (Reactome) | |||
| ATP | REACT_115934 (Reactome) | |||
| ATP | REACT_115965 (Reactome) | |||
| ATP | REACT_116132 (Reactome) | |||
| E2 congugating enzymes | REACT_115543 (Reactome) | |||
| EIF4E2 | REACT_115679 (Reactome) | |||
| EIF4F | Arrow | REACT_115968 (Reactome) | ||
| FLNB | REACT_115658 (Reactome) | |||
| IRF3 | REACT_115934 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | REACT_115543 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | REACT_115658 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | REACT_115679 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | REACT_115843 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | REACT_115890 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | REACT_115934 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | REACT_115965 (Reactome) | |||
| ISG15
UBCH8 ISG15 E3 ligase | mim-catalysis | REACT_115543 (Reactome) | ||
| ISG15
UBCH8 ISG15 E3 ligase | mim-catalysis | REACT_115658 (Reactome) | ||
| ISG15
UBCH8 ISG15 E3 ligase | mim-catalysis | REACT_115843 (Reactome) | ||
| ISG15
UBCH8 ISG15 E3 ligase | mim-catalysis | REACT_115890 (Reactome) | ||
| ISG15
UBCH8 ISG15 E3 ligase | mim-catalysis | REACT_115934 (Reactome) | ||
| ISG15
UBCH8 ISG15 E3 ligase | mim-catalysis | REACT_115965 (Reactome) | ||
| ISG15 UBCH8 | Arrow | REACT_115873 (Reactome) | ||
| ISG15 UBCH8 | REACT_116157 (Reactome) | |||
| ISG15 UBE1L | Arrow | REACT_116132 (Reactome) | ||
| ISG15 UBE1L | REACT_115873 (Reactome) | |||
| ISG15 E3 ligases | Arrow | REACT_115543 (Reactome) | ||
| ISG15 E3 ligases | Arrow | REACT_115658 (Reactome) | ||
| ISG15 E3 ligases | Arrow | REACT_115843 (Reactome) | ||
| ISG15 E3 ligases | Arrow | REACT_115890 (Reactome) | ||
| ISG15 E3 ligases | Arrow | REACT_115934 (Reactome) | ||
| ISG15 E3 ligases | Arrow | REACT_115965 (Reactome) | ||
| ISG15 E3 ligases | REACT_116157 (Reactome) | |||
| ISG15 targets | Arrow | REACT_115684 (Reactome) | ||
| ISG15 targets | REACT_115890 (Reactome) | |||
| ISG15 | REACT_115975 (Reactome) | |||
| ISG15 | REACT_116132 (Reactome) | |||
| ISG15 | TBar | REACT_115813 (Reactome) | ||
| ISGylated 4EHP mRNA | Arrow | REACT_115968 (Reactome) | ||
| ISGylated 4EHP | REACT_115968 (Reactome) | |||
| ISGylated E2 conjugating enzymes | Arrow | REACT_115543 (Reactome) | ||
| ISGylated Filamin B | Arrow | REACT_115658 (Reactome) | ||
| ISGylated IRF3 | Arrow | REACT_115934 (Reactome) | ||
| ISGylated IRF3 | TBar | REACT_24932 (Reactome) | ||
| ISGylated NS1 | Arrow | REACT_115965 (Reactome) | ||
| ISGylated NS1 | TBar | REACT_115827 (Reactome) | ||
| ISGylated PP2CB | Arrow | REACT_115843 (Reactome) | ||
| ISGylated host proteins | Arrow | REACT_115890 (Reactome) | ||
| Importin | REACT_115827 (Reactome) | |||
| N-myristoyl GAG | REACT_115813 (Reactome) | |||
| NEDD4 | REACT_115975 (Reactome) | |||
| NS1 Homodimer | REACT_115827 (Reactome) | |||
| NS1 | REACT_115965 (Reactome) | |||
| Nuclear Pore Complex | mim-catalysis | REACT_115827 (Reactome) | ||
| PPM1B | REACT_115843 (Reactome) | |||
| PPi | Arrow | REACT_115543 (Reactome) | ||
| PPi | Arrow | REACT_115658 (Reactome) | ||
| PPi | Arrow | REACT_115843 (Reactome) | ||
| PPi | Arrow | REACT_115890 (Reactome) | ||
| PPi | Arrow | REACT_115934 (Reactome) | ||
| PPi | Arrow | REACT_115965 (Reactome) | ||
| PPi | Arrow | REACT_116132 (Reactome) | ||
| REACT_115543 (Reactome) | Ubiquitin conjugating E2 enzymes UBC13 and UBCH6 are targets for ISGylation. This suppresses the ubiquitin-conjugating activity of both UBC13 and UBCH6. This modification may play an important role in the control of signal transduction pathways, such as the NF-kB pathway, which are associated with K63-linked polyubiquitination (Takeuchi et al, 2005). | |||
| REACT_115658 (Reactome) | ISG15 negatively regulates the scaffold protein filamin B. In response to type I IFNs, filamin B recruits RAC1, MEKK1, and MKK4, enhancing their sequential activation and thereby promoting JNK activation and apoptosis. ISGylation of filamin B leads to the disassociation of RAC1, MEKK1, and MKK4 from the scaffold, preventing type I IFN dependent JNK activation and apoptosis. It has been suggested that this inhibition of apoptosis may protect uninfected bystander cells from IFN-mediated apoptosis (Jeon et al, 2009). | |||
| REACT_115679 (Reactome) | 4EHP is a member of eukaryotic translation initiation factor 4E (eIF4E) family that acts as an mRNA 5' cap structure-binding protein and suppresses translation. 4EHP is one of the targets of ISG15 and ISGylated 4EHP has a much higher cap structure-binding activity. | |||
| REACT_115684 (Reactome) | Ubiquitin specific protease 18 (USP18/UBP43) is the major ISG15 deconjugating enzyme. It removes ISG15 from ISGylated proteins. ISG15-specific protease activity of this enzyme is crucial for proper cellular balance of ISG15-conjugated proteins. However, it is not required for processing pre-ISG15 to the mature form. Furthermore, USP18 inhibits type I interferon signaling independent of its ISG15 deconjugating enzyme activity. Several viral proteins were also reported with de-ISGylation activity. | |||
| REACT_115813 (Reactome) | Cytosolic N-myristoyl Gag polyprotein is conjugated with a single molecule of ubiquitin. Conjugation is typically to one of two lysine residues in the p6 domain of Gag but can be to lysine residues in the MA, CA, NC, and SP2 domains of the protein. The specific host cell E2 and E3 proteins that mediate Gag ubiquitination have not been identified. The same studies that first identified the p6 ubiquitination sites in Gag also called the biological significance of Gag ubiquitination into question by demonstrating that Gag proteins in which the p6 ubiquitination sites had been removed by mutagenesis could still assemble efficiently into infectious viral particles (Ott et al. 1998, 2000). More recent work, however, has identified additional ubiquitination sites throughout the C-terminal region of the Gag polyprotein, and when all of these sites are removed by mutagenesis, both viral assembly involving the mutant Gag polyprotein and infectivity of the resulting viral particles are sharply reduced (Gottwein et al. 2006). Note: Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red. | |||
| REACT_115827 (Reactome) | Influenza A virus nonstructural protein 1 (NS1A) is a multifunctional protein that exists as a dimer and is involved in the inhibition of host cell antiviral pre-mRNA processing and counteracts host cell antiviral responses. Unlike most other RNA viruses, influenza viruses replicate in the nucleus of the host cells. NS1A protein carries two nuclear localization signal (NLS) elements and these sequence elements are recognized by importin-alpha/beta. In the cytoplasm NS1A binds to importin-alpha/beta and these protein complexes are then translocated into the nucleus through the nuclear pore complex (NPC). Note:Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red. | |||
| REACT_115843 (Reactome) | Protein phosphatase 1 beta (PPM1B/PP2CB) is a target for ISG15. PP2CB dephosphorylates TAK1 and suppresses TAK1/TAB1-mediated IkB alpha degradation and thereby controls the NF-kB signaling pathway, which plays a critical role in innate and adaptive immunity and cancer. ISGylation of PP2CB may block the suppressive function of the phosphatase against TAK1/TAB1 mediated NF-kB activation. | |||
| REACT_115873 (Reactome) | Activated ISG15 linked to UBE1L is transferred to the E2 conjugating enzyme UBCH8. | |||
| REACT_115890 (Reactome) | Many host proteins are targets for ISGylation including constitutively expressed proteins involved in various cellular pathways such as immunity, RNA splicing, chromatin remodeling/polymerase II transcription, stress responses and translation. Many ISG15 target proteins are IFN alpha/beta-induced antiviral proteins such as PKR, MxA, IRF3, and RIG-I, also included are several key regulators of signal transduction such as PLC gamma1, JAK1, STAT1 and ERK1. The contribution of most of these modified proteins to antiviral activity is unclear because the fate of the vast majority of ISGylated target proteins is unknown. | |||
| REACT_115934 (Reactome) | The transcription factor IRF3 is a target for ISGylation. Conjugation of ISG15 positively regulates IRF3 and thereby promotes induction of type I interferons. ISGylation of IRF3 prevents the binding of PIN1, a protein that promotes IRF3 ubiquitination and subsequent degradation. | |||
| REACT_115965 (Reactome) | Some viral proteins are also targeted for ISGylation. The well studied viral protein ISGylation is the modification of the influenza A viral protein NS1, which functions as an IFN antagonist during viral infection. Studies identified seven lysine residues in NS1 as potential ISGylation sites among which K41 (Zhao et al. 2010), K126 and K217 (Tang et al. 2010) were found to be critical. ISGylation at these sites disrupts NS1 association with importin-alpha, a protein required for the nuclear import of NS1. | |||
| REACT_115968 (Reactome) | Eukaryotic translation initiation factor 4F (eIF4F) is a protein complex that mediates recruitment of ribosomes to mRNA (Gingras et al. 1999). eIF4F contains complex of cap-binding protein eIF4E, scaffold protein eIF4G, and RNA helicase eIF4A. There are three eIF4E-family members in mammals termed eIF4E-1 (eIF4E), eIF4E2 (4EHP), and eIF4E3, of which both eIF4E and eIF4E3 are able to bind to eIF4G to facilitate translation initiation. However, 4EHP does not interact with eIF4G and thus cannot function in ribosome recruitment. 4EHP competes with eIF4E or eIF4E3 for binding to the RNA 5? cap structure and prevents translation initiation. ISGylated 4EHP has a much higher cap structure binding activity, suggesting a regulatory function of ISGylation in protein translation during immune responses (Okumura et al. 2007, Joshi et al. 2004). | |||
| REACT_115975 (Reactome) | Ebola virus VP40 virus-like particles (VLPs) requires the interaction of overlapping L-domains in the VP40 protein with host NEDD4 protein for efficient budding. Mono-ubiquitination of VP40 mediated by the NEDD4 E3 ligase is thought to be required for virus budding and release. ISG15 interacts with NEDD4 and inhibits the transfer of ubiquitin from the E2 enzyme to NEDD4. This prevents NEDD4-mediated ubiquitination of Ebola virus VP40 which is required for virion release. | |||
| REACT_116132 (Reactome) | Ubiquitin ligase UBE1L is the ISG15 activating enzyme. UBE1L activates ISG15 in an ATP-dependent process that links UBE1L to ISG15 via a thioester bond. Arginine 153 (R153) in human ISG15 is identified as the key residue for ISG15 and UBE1L's interaction. | |||
| REACT_116157 (Reactome) | Ubiquitin ligase HERC5/CEB1 appears to be the predominant E3 ligase for ISGylation; EFP and HHARI/ARIH1 have also been reported as ISG15 E3 ligases. The E3 ligase recognizes specific target substrates and mediates the transfer of ISG15 from E2 to the substrate. | |||
| REACT_24932 (Reactome) | PIN1 acts as a negative regulator of IFN induction. Its association with IRF3 leads to ubiquitin-mediated proteosomal degradation of IRF3. PIN1 on its own does not have ubiquitin activation, transfer or ligase activities. Exactly how this IRF3 degradation is achieved is unclear at present. Immunoprecipitation of ubiquitin followed by immunoblot analysis for IRF3 demonstrated that polyubiquitination of IRF3 was induced by RNA stimulation and that polyubiquitination was augmented by PIN1 expression and abrogated by expression of PIN1-specific shRNA. | |||
| UBA7 | Arrow | REACT_115873 (Reactome) | ||
| UBA7 | REACT_116132 (Reactome) | |||
| UBA7 | mim-catalysis | REACT_116132 (Reactome) | ||
| UBE2L6 | Arrow | REACT_115543 (Reactome) | ||
| UBE2L6 | Arrow | REACT_115658 (Reactome) | ||
| UBE2L6 | Arrow | REACT_115843 (Reactome) | ||
| UBE2L6 | Arrow | REACT_115890 (Reactome) | ||
| UBE2L6 | Arrow | REACT_115934 (Reactome) | ||
| UBE2L6 | Arrow | REACT_115965 (Reactome) | ||
| UBE2L6 | REACT_115873 (Reactome) | |||
| UBE2L6 | mim-catalysis | REACT_115873 (Reactome) | ||
| USP18 | mim-catalysis | REACT_115684 (Reactome) | ||
| Ub | REACT_115813 (Reactome) | |||
| eIF4F mRNA | REACT_115968 (Reactome) | |||
| polypeptide | Arrow | REACT_115684 (Reactome) |
