ISG15
entrez
9636
canonical
uniprot
P05161
canonical
ensembl
ENSG00000187608
resolver
ensp
ENSP00000496832
resolver
ensp
ENSP00000614301
resolver
enst
ENST00000649529
resolver
enst
ENST00000944242
resolver
genesymbol
ISG15
resolver
genesymbol_syn
G1P2
resolver
genesymbol_syn
UCRP
resolver
hgnc
HGNC:4053
resolver
uniprot
Q5SVA4
resolver
uniprot
Q7Z2G2
resolver
uniprot
Q96GF0
resolver
uniprot_entry
ISG15_HUMAN
resolver
uniprot_sec
Q5SVA4
resolver
uniprot_sec
Q7Z2G2
resolver
uniprot_sec
Q96GF0
resolver
amino_acid_sequence
MGWDLTVKMLAGNEFQVSLSSSMSVSELKAQITQKIGVHAFQQRLAVHPSGVALQDRVPLASQGLGPGSTVLLVVDKCDEPLSILVRNNKGRSSTYEVRLTQTVAHLKQQVSGLEGVQDDLFWLTFEGKPLEDQLPLGEYGLKPLSTVFMNLRLRGGGTEPGGRS
uniprot
proteins
disease_involvement
DISEASE: Immunodeficiency 38, with basal ganglia calcification (IMD38) [MIM:616126]: A 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. {ECO:0000269|PubMed:22859821}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
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, 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). {ECO:0000269|PubMed:1373138, ECO:0000269|PubMed:16009940, ECO:0000269|PubMed:16112642, ECO:0000269|PubMed:16428300, ECO:0000269|PubMed:16434471, ECO:0000269|PubMed:16872604, ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:19270716, ECO:0000269|PubMed:19357168, ECO:0000269|PubMed:2005397, ECO:0000269|PubMed:20133869, ECO:0000269|PubMed:20308324, ECO:0000269|PubMed:20639253, ECO:0000269|PubMed:21543490, ECO:0000269|PubMed:22693631, ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:27564865, ECO:0000269|PubMed:29100055, ECO:0000269|PubMed:33727702, ECO:0000269|PubMed:39465252, ECO:0000269|PubMed:7526157, ECO:0000269|PubMed:8550581}.
uniprot
proteins
mass_dalton
17888
uniprot
proteins
mutagenesis
MUTAGEN 44; /note="R->A: Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases."; /evidence="ECO:0000269|PubMed:29100055"; MUTAGEN 83; /note="S->A: Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases."; /evidence="ECO:0000269|PubMed:29100055"; MUTAGEN 96; /note="Y->L: Reduces ISG15 signaling. Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases; when associated with D-102."; /evidence="ECO:0000269|PubMed:29100055"; MUTAGEN 99; /note="R->A: Strongly reduces ISG15 signaling and abolishes interaction with ITGAL."; /evidence="ECO:0000269|PubMed:29100055"; MUTAGEN 101; /note="T->A: Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases."; /evidence="ECO:0000269|PubMed:29100055"; MUTAGEN 102; /note="Q->D: Reduces ISG15 signaling. Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases; when associated with L-96."; /evidence="ECO:0000269|PubMed:29100055"; MUTAGEN 103; /note="T->A: Strongly reduces ISG15 signaling and abolishes interaction with ITGAL."; /evidence="ECO:0000269|PubMed:29100055
uniprot
proteins
post_translational_modification
PTM: S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins. {ECO:0000269|PubMed:18606809}.; 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. {ECO:0000269|PubMed:2477469, ECO:0000269|PubMed:3350799}.
uniprot
proteins
pubmed
11157743
uniprot
proteins
pubmed
11788588
uniprot
proteins
pubmed
1373138
uniprot
proteins
pubmed
15131269
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15917233
uniprot
proteins
pubmed
16009940
uniprot
proteins
pubmed
16112642
uniprot
proteins
pubmed
16428300
uniprot
proteins
pubmed
16434471
uniprot
proteins
pubmed
16710414
uniprot
proteins
pubmed
16872604
uniprot
proteins
pubmed
18305167
uniprot
proteins
pubmed
18356159
uniprot
proteins
pubmed
18606809
uniprot
proteins
pubmed
19270716
uniprot
proteins
pubmed
19357168
uniprot
proteins
pubmed
19680460
uniprot
proteins
pubmed
2005397
uniprot
proteins
pubmed
20133869
uniprot
proteins
pubmed
20153823
uniprot
proteins
pubmed
20308324
uniprot
proteins
pubmed
20639253
uniprot
proteins
pubmed
20946978
uniprot
proteins
pubmed
21190487
uniprot
proteins
pubmed
21245344
uniprot
proteins
pubmed
21266548
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21543490
uniprot
proteins
pubmed
21994614
uniprot
proteins
pubmed
22666250
uniprot
proteins
pubmed
22693631
uniprot
proteins
pubmed
22859821
uniprot
proteins
pubmed
22906767
uniprot
proteins
pubmed
22964713
uniprot
proteins
pubmed
23229543
uniprot
proteins
pubmed
23414970
uniprot
proteins
pubmed
23579383
uniprot
proteins
pubmed
24257616
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
2440890
uniprot
proteins
pubmed
2477469
uniprot
proteins
pubmed
27564865
uniprot
proteins
pubmed
29100055
uniprot
proteins
pubmed
3087979
uniprot
proteins
pubmed
3350799
uniprot
proteins
pubmed
33727702
uniprot
proteins
pubmed
3476954
uniprot
proteins
pubmed
39465252
uniprot
proteins
pubmed
7490683
uniprot
proteins
pubmed
7526157
uniprot
proteins
pubmed
8550581
uniprot
proteins
sequence_length
165
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:39465252}. Secreted {ECO:0000269|PubMed:22859821}. Note=Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins.
uniprot
proteins