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Details on Person UniProt:P05161 ISG15
| Class:Id | ReferenceGeneProduct:66900 |
|---|---|
| _chainChangeLog | initiator methionine:1 added on Fri February 6 2015;chain:2-157 added on Fri February 6 2015;propeptide:158-165 added on Fri February 6 2015;initiator methionine:1 for 66900 removed on Fri Nov 03 2023;initiator methionine: for 66900 added on Fri Nov 03 2023;initiator methionine: for 66900 removed on Fri Aug 15 2025;initiator methionine:1 for 66900 added on Fri Aug 15 2025 |
| _displayName | UniProt:P05161 ISG15 |
| _timestamp | 2025-08-15 22:08:54 |
| chain | initiator methionine:1 chain:2-157 propeptide:158-165 |
| checksum | B6858A15AB0FFFDE |
| comment | FUNCTION Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein (PubMed:27564865, PubMed:39465252). ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein (PubMed:33727702). Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses (PubMed:33727702). Can also isgylate: EIF2AK2/PKR which results in its activation, RIGI which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL (PubMed:29100055).SUBUNIT Homodimer; disulfide-linked (PubMed:2440890). Interacts with, and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (PubMed:11157743, PubMed:15131269). Interacts with NEDD4 (PubMed:18305167). Interacts with PARP12; this interaction inhibits PINK1/Parkin-dependent mitophagy (PubMed:39465252).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein E3.SUBUNIT (Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.SUBUNIT (Microbial infection) Interacts (via C-terminus) with Crimean-Congo hemorrhagic fever virus (CCHFV) RNA-directed RNA polymerase L (via N-terminus); the deISGylase activity of the viral protein interferes with antiviral signaling pathways mediated by NF-kappaB and IRF signalings.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL26; this interaction inhibits global protein ISGylation.INTERACTION Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins.TISSUE SPECIFICITY Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-cancerous tissue. In bladder cancer, the increase in expression exhibits a striking positive correlation with more advanced stages of the disease.INDUCTION Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses.DOMAIN Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein (PubMed:18356159).PTM S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.PTM Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases.DISEASE The disease is caused by variants affecting the gene represented in this entry.ONLINE INFORMATION On guard - Issue 240 of October 2021 |
| description | recommendedName: Ubiquitin-like protein ISG15 alternativeName: Interferon-induced 15 kDa protein alternativeName: Interferon-induced 17 kDa protein shortName: IP17 alternativeName: Ubiquitin cross-reactive protein shortName: hUCRP |
| geneName | ISG15 G1P2 UCRP |
| identifier | P05161 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Antiviral defense Cytoplasm Direct protein sequencing Disulfide bond Host-virus interaction Immunity Innate immunity Isopeptide bond Proteomics identification Reference proteome Repeat S-nitrosylation Secreted Ubl conjugation pathway |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 |
| name | ISG15 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8962205] ENSEMBL:ENSG00000187608 ISG15 [Homo sapiens] |
| secondaryIdentifier | ISG15_HUMAN Q5SVA4 Q7Z2G2 Q96GF0 |
| sequenceLength | 165 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:936552] ISG15 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:5653665] ISG15 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:5653744] K168-PCNA-G157-ISG15 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:5653745] K164-PCNA-G157-ISG15 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:9968640] lysyl-G157-ISG15 [cytosol] [Homo sapiens] |
| (referenceSequence) | [InterChainCrosslinkedResidue:5653749] Inter-chain Crosslink via N6-glycyl-L-lysine at 157 and 168 [InterChainCrosslinkedResidue:5653752] Inter-chain Crosslink via N6-glycyl-L-lysine at 157 and 164 [ModifiedResidue:9968639] glycine amide at 157 |
| (secondReferenceSequence) | [InterChainCrosslinkedResidue:5653746] Inter-chain Crosslink via N6-glycyl-L-lysine at 164 and 157 [InterChainCrosslinkedResidue:5653748] Inter-chain Crosslink via N6-glycyl-L-lysine at 168 and 157 |
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No pathways have been reviewed or authored by UniProt:P05161 ISG15 (66900)
