P05161 · ISG15_HUMAN
- ProteinUbiquitin-like protein ISG15
- GeneISG15
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids165 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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).
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).
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).
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 153 | Interacts with activating enzyme | ||||
Sequence: R |
GO annotations
Keywords
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameUbiquitin-like protein ISG15
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP05161
- Secondary accessions
Proteomes
Organism-specific databases
Disease & Variants
Involvement in disease
Immunodeficiency 38, with basal ganglia calcification (IMD38)
- Note
- DescriptionA primary immunodeficiency predisposing individuals to severe clinical disease upon infection with weakly virulent mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines. Patients are also susceptible to Salmonella and Mycobacterium tuberculosis infections. Affected individuals have intracranial calcification.
- See alsoMIM:616126
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 44 | Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases. | ||||
Sequence: R → A | ||||||
Natural variant | VAR_016181 | 83 | in dbSNP:rs1921 | |||
Sequence: S → N | ||||||
Mutagenesis | 83 | Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases. | ||||
Sequence: S → A | ||||||
Mutagenesis | 96 | Reduces ISG15 signaling. Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases; when associated with D-102. | ||||
Sequence: Y → L | ||||||
Mutagenesis | 99 | Strongly reduces ISG15 signaling and abolishes interaction with ITGAL. | ||||
Sequence: R → A | ||||||
Mutagenesis | 101 | Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases. | ||||
Sequence: T → A | ||||||
Mutagenesis | 102 | Reduces ISG15 signaling. Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases; when associated with L-96. | ||||
Sequence: Q → D | ||||||
Mutagenesis | 103 | Strongly reduces ISG15 signaling and abolishes interaction with ITGAL. | ||||
Sequence: T → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 202 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, chain, modified residue, disulfide bond, cross-link, propeptide.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Initiator methionine | 1 | Removed | ||||
Sequence: M | ||||||
Chain | PRO_0000035986 | 2-157 | Ubiquitin-like protein ISG15 | |||
Sequence: GWDLTVKMLAGNEFQVSLSSSMSVSELKAQITQKIGVHAFQQRLAVHPSGVALQDRVPLASQGLGPGSTVLLVVDKCDEPLSILVRNNKGRSSTYEVRLTQTVAHLKQQVSGLEGVQDDLFWLTFEGKPLEDQLPLGEYGLKPLSTVFMNLRLRGG | ||||||
Modified residue | 78 | S-nitrosocysteine; alternate | ||||
Sequence: C | ||||||
Disulfide bond | 78 | Interchain (with C-87 in UBE2N); alternate | ||||
Sequence: C | ||||||
Cross-link | 157 | Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins) | ||||
Sequence: G | ||||||
Propeptide | PRO_0000035987 | 158-165 | Removed in mature form | |||
Sequence: GTEPGGRS |
Post-translational modification
S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.
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.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
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.
Gene expression databases
Organism-specific databases
Interaction
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, and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (PubMed:11157743, PubMed:15131269).
Interacts with NEDD4 (PubMed:18305167).
(Microbial infection) Interacts with vaccinia virus protein E3.
(Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.
(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.
(Microbial infection) Interacts with human cytomegalovirus protein UL26; this interaction inhibits global protein ISGylation.
Binary interactions
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, motif, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 2-78 | Ubiquitin-like 1 | ||||
Sequence: GWDLTVKMLAGNEFQVSLSSSMSVSELKAQITQKIGVHAFQQRLAVHPSGVALQDRVPLASQGLGPGSTVLLVVDKC | ||||||
Domain | 79-157 | Ubiquitin-like 2 | ||||
Sequence: DEPLSILVRNNKGRSSTYEVRLTQTVAHLKQQVSGLEGVQDDLFWLTFEGKPLEDQLPLGEYGLKPLSTVFMNLRLRGG | ||||||
Motif | 152-157 | LRLRGG | ||||
Sequence: LRLRGG | ||||||
Region | 153-157 | Involved in the ligation of specific target proteins | ||||
Sequence: RLRGG |
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).
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length165
- Mass (Da)17,888
- Last updated2007-01-23 v5
- ChecksumB6858A15AB0FFFDE
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A096LNZ9 | A0A096LNZ9_HUMAN | ISG15 | 143 | ||
A0A096LPJ4 | A0A096LPJ4_HUMAN | ISG15 | 157 |
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 35 | in Ref. 2; AAA36128 | ||||
Sequence: K → N |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M13755 EMBL· GenBank· DDBJ | AAA36038.1 EMBL· GenBank· DDBJ | mRNA | ||
M21786 EMBL· GenBank· DDBJ | AAA36128.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY168648 EMBL· GenBank· DDBJ | AAN86983.1 EMBL· GenBank· DDBJ | mRNA | ||
BT007297 EMBL· GenBank· DDBJ | AAP35961.1 EMBL· GenBank· DDBJ | mRNA | ||
AL645608 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471183 EMBL· GenBank· DDBJ | EAW56295.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC009507 EMBL· GenBank· DDBJ | AAH09507.1 EMBL· GenBank· DDBJ | mRNA |