UniProtKB - P05161 (ISG15_HUMAN)
Ubiquitin-like protein ISG15
ISG15
Functioni
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. 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, DDX58/RIG-I 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).
21 PublicationsSites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 153 | Interacts with activating enzymeBy similarity | 1 |
GO - Molecular functioni
- integrin binding Source: UniProtKB
- protein tag Source: GO_Central
- structural constituent of ribosome Source: GO_Central
- ubiquitin protein ligase binding Source: GO_Central
GO - Biological processi
- defense response to bacterium Source: UniProtKB
- defense response to virus Source: UniProtKB
- integrin-mediated signaling pathway Source: UniProtKB
- ISG15-protein conjugation Source: UniProtKB
- modification-dependent protein catabolic process Source: GO_Central
- negative regulation of protein ubiquitination Source: UniProtKB
- negative regulation of type I interferon-mediated signaling pathway Source: ARUK-UCL
- negative regulation of viral genome replication Source: UniProtKB
- positive regulation of bone mineralization Source: UniProtKB
- positive regulation of erythrocyte differentiation Source: Ensembl
- positive regulation of interferon-beta production Source: UniProtKB
- positive regulation of interferon-gamma production Source: UniProtKB
- positive regulation of interleukin-10 production Source: UniProtKB
- positive regulation of protein oligomerization Source: UniProtKB
- protein localization to mitochondrion Source: UniProtKB
- regulation of interferon-gamma production Source: UniProtKB
- response to type I interferon Source: UniProtKB
- response to virus Source: UniProtKB
Keywordsi
Biological process | Antiviral defense, Host-virus interaction, Immunity, Innate immunity, Ubl conjugation pathway |
Enzyme and pathway databases
PathwayCommonsi | P05161 |
Reactomei | R-HSA-1169408, ISG15 antiviral mechanism R-HSA-168276, NS1 Mediated Effects on Host Pathways R-HSA-168928, DDX58/IFIH1-mediated induction of interferon-alpha/beta R-HSA-5656169, Termination of translesion DNA synthesis R-HSA-909733, Interferon alpha/beta signaling R-HSA-936440, Negative regulators of DDX58/IFIH1 signaling |
SignaLinki | P05161 |
Names & Taxonomyi
Protein namesi | Recommended name: Ubiquitin-like protein ISG15Alternative name(s): Interferon-induced 15 kDa protein Interferon-induced 17 kDa protein Short name: IP17 Ubiquitin cross-reactive protein Short name: hUCRP |
Gene namesi | |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:4053, ISG15 |
MIMi | 147571, gene |
neXtProti | NX_P05161 |
VEuPathDBi | HostDB:ENSG00000187608 |
Subcellular locationi
Cytosol
- cytosol Source: Reactome
- cytosolic small ribosomal subunit Source: GO_Central
Extracellular region or secreted
- extracellular region Source: UniProtKB
Nucleus
- nucleoplasm Source: Reactome
- nucleus Source: GO_Central
Other locations
- cytoplasm Source: GO_Central
Keywords - Cellular componenti
Cytoplasm, SecretedPathology & Biotechi
Involvement in diseasei
Immunodeficiency 38, with basal ganglia calcification (IMD38)1 Publication
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 44 | R → A: Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases. 1 Publication | 1 | |
Mutagenesisi | 83 | S → A: Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases. 1 Publication | 1 | |
Mutagenesisi | 96 | 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. 1 Publication | 1 | |
Mutagenesisi | 99 | R → A: Strongly reduces ISG15 signaling and abolishes interaction with ITGAL. 1 Publication | 1 | |
Mutagenesisi | 101 | T → A: Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases. 1 Publication | 1 | |
Mutagenesisi | 102 | 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. 1 Publication | 1 | |
Mutagenesisi | 103 | T → A: Strongly reduces ISG15 signaling and abolishes interaction with ITGAL. 1 Publication | 1 |
Organism-specific databases
DisGeNETi | 9636 |
MalaCardsi | ISG15 |
MIMi | 616126, phenotype |
OpenTargetsi | ENSG00000187608 |
Orphaneti | 319563, Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency |
PharmGKBi | PA28465 |
Miscellaneous databases
Pharosi | P05161, Tbio |
Genetic variation databases
BioMutai | ISG15 |
DMDMi | 52001470 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Initiator methioninei | Removed1 Publication | |||
ChainiPRO_0000035986 | 2 – 157 | Ubiquitin-like protein ISG15Add BLAST | 156 | |
PropeptideiPRO_0000035987 | 158 – 165 | Removed in mature form | 8 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 78 | S-nitrosocysteine; alternate1 Publication | 1 | |
Disulfide bondi | 78 | Interchain (with C-87 in UBE2N); alternate1 Publication | ||
Cross-linki | 157 | Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins)PROSITE-ProRule annotation |
Post-translational modificationi
Keywords - PTMi
Disulfide bond, Isopeptide bond, S-nitrosylationProteomic databases
EPDi | P05161 |
jPOSTi | P05161 |
MassIVEi | P05161 |
MaxQBi | P05161 |
PaxDbi | P05161 |
PeptideAtlasi | P05161 |
PRIDEi | P05161 |
ProteomicsDBi | 51809 |
TopDownProteomicsi | P05161 |
PTM databases
GlyGeni | P05161, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P05161 |
PhosphoSitePlusi | P05161 |
Expressioni
Tissue specificityi
Inductioni
Gene expression databases
Bgeei | ENSG00000187608, Expressed in epithelium of bronchus and 240 other tissues |
ExpressionAtlasi | P05161, baseline and differential |
Genevisiblei | P05161, HS |
Organism-specific databases
HPAi | ENSG00000187608, Tissue enhanced (salivary) |
Interactioni
Subunit structurei
(Microbial infection) Interacts with vaccinia virus protein E3.
1 Publication(Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.
1 PublicationBinary interactionsi
P05161
GO - Molecular functioni
- integrin binding Source: UniProtKB
- ubiquitin protein ligase binding Source: GO_Central
Protein-protein interaction databases
BioGRIDi | 114995, 397 interactors |
DIPi | DIP-29814N |
IntActi | P05161, 64 interactors |
MINTi | P05161 |
STRINGi | 9606.ENSP00000368699 |
Miscellaneous databases
RNActi | P05161, protein |
Structurei
Secondary structure
3D structure databases
AlphaFoldDBi | P05161 |
BMRBi | P05161 |
SMRi | P05161 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P05161 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 2 – 78 | Ubiquitin-like 1PROSITE-ProRule annotationAdd BLAST | 77 | |
Domaini | 79 – 157 | Ubiquitin-like 2PROSITE-ProRule annotationAdd BLAST | 79 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 153 – 157 | Involved in the ligation of specific target proteinsBy similarity | 5 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 152 – 157 | LRLRGG | 6 |
Domaini
Keywords - Domaini
RepeatPhylogenomic databases
eggNOGi | KOG0001, Eukaryota |
GeneTreei | ENSGT00940000162007 |
InParanoidi | P05161 |
OMAi | QCTVFMN |
OrthoDBi | 1367357at2759 |
PhylomeDBi | P05161 |
TreeFami | TF338379 |
Family and domain databases
InterProi | View protein in InterPro IPR000626, Ubiquitin-like_dom IPR029071, Ubiquitin-like_domsf IPR019956, Ubiquitin_dom |
Pfami | View protein in Pfam PF00240, ubiquitin, 2 hits |
PRINTSi | PR00348, UBIQUITIN |
SMARTi | View protein in SMART SM00213, UBQ, 2 hits |
SUPFAMi | SSF54236, SSF54236, 2 hits |
PROSITEi | View protein in PROSITE PS50053, UBIQUITIN_2, 2 hits |
(1+)i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All
10 20 30 40 50
MGWDLTVKML AGNEFQVSLS SSMSVSELKA QITQKIGVHA FQQRLAVHPS
60 70 80 90 100
GVALQDRVPL ASQGLGPGST VLLVVDKCDE PLSILVRNNK GRSSTYEVRL
110 120 130 140 150
TQTVAHLKQQ VSGLEGVQDD LFWLTFEGKP LEDQLPLGEY GLKPLSTVFM
160
NLRLRGGGTE PGGRS
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketA0A096LPJ4 | A0A096LPJ4_HUMAN | Ubiquitin-like protein ISG15 | ISG15 | 157 | Annotation score: | ||
A0A096LNZ9 | A0A096LNZ9_HUMAN | Ubiquitin-like protein ISG15 | ISG15 | 143 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 35 | K → N in AAA36128 (PubMed:3476954).Curated | 1 |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_016181 | 83 | S → N3 PublicationsCorresponds to variant dbSNP:rs1921EnsemblClinVar. | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | M13755 mRNA Translation: AAA36038.1 M21786 Genomic DNA Translation: AAA36128.1 AY168648 mRNA Translation: AAN86983.1 BT007297 mRNA Translation: AAP35961.1 AL645608 Genomic DNA No translation available. CH471183 Genomic DNA Translation: EAW56295.1 BC009507 mRNA Translation: AAH09507.1 |
CCDSi | CCDS6.1 |
PIRi | A28304, A28138 |
RefSeqi | NP_005092.1, NM_005101.3 |
Genome annotation databases
Ensembli | ENST00000649529.1; ENSP00000496832.1; ENSG00000187608.10 |
GeneIDi | 9636 |
KEGGi | hsa:9636 |
MANE-Selecti | ENST00000649529.1; ENSP00000496832.1; NM_005101.4; NP_005092.1 |
UCSCi | uc001acj.5, human |
Similar proteinsi
Cross-referencesi
Web resourcesi
Protein Spotlight On guard - Issue 240 of October 2021 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | M13755 mRNA Translation: AAA36038.1 M21786 Genomic DNA Translation: AAA36128.1 AY168648 mRNA Translation: AAN86983.1 BT007297 mRNA Translation: AAP35961.1 AL645608 Genomic DNA No translation available. CH471183 Genomic DNA Translation: EAW56295.1 BC009507 mRNA Translation: AAH09507.1 |
CCDSi | CCDS6.1 |
PIRi | A28304, A28138 |
RefSeqi | NP_005092.1, NM_005101.3 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
1Z2M | X-ray | 2.50 | A | 1-155 | [»] | |
2HJ8 | NMR | - | A | 79-157 | [»] | |
3PHX | X-ray | 1.60 | B | 79-156 | [»] | |
3PSE | X-ray | 2.30 | B | 1-156 | [»] | |
3R66 | X-ray | 2.30 | C/D | 1-157 | [»] | |
3RT3 | X-ray | 2.01 | B | 1-158 | [»] | |
3SDL | X-ray | 2.29 | C/D | 1-157 | [»] | |
5TL6 | X-ray | 2.62 | A/C | 80-157 | [»] | |
5W8T | X-ray | 2.76 | B/D | 80-156 | [»] | |
5W8U | X-ray | 2.41 | B/D | 80-156 | [»] | |
6BI8 | X-ray | 3.00 | C/D | 1-156 | [»] | |
6FFA | X-ray | 1.50 | B | 79-155 | [»] | |
6XA9 | X-ray | 2.90 | B/D/F | 79-157 | [»] | |
7RBS | X-ray | 2.98 | B/D/F/H/J | 2-157 | [»] | |
7S6P | X-ray | 2.15 | A/B/C/D/E/F | 2-157 | [»] | |
AlphaFoldDBi | P05161 | |||||
BMRBi | P05161 | |||||
SMRi | P05161 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 114995, 397 interactors |
DIPi | DIP-29814N |
IntActi | P05161, 64 interactors |
MINTi | P05161 |
STRINGi | 9606.ENSP00000368699 |
PTM databases
GlyGeni | P05161, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P05161 |
PhosphoSitePlusi | P05161 |
Genetic variation databases
BioMutai | ISG15 |
DMDMi | 52001470 |
Proteomic databases
EPDi | P05161 |
jPOSTi | P05161 |
MassIVEi | P05161 |
MaxQBi | P05161 |
PaxDbi | P05161 |
PeptideAtlasi | P05161 |
PRIDEi | P05161 |
ProteomicsDBi | 51809 |
TopDownProteomicsi | P05161 |
Protocols and materials databases
Antibodypediai | 809, 572 antibodies from 40 providers |
DNASUi | 9636 |
Genome annotation databases
Ensembli | ENST00000649529.1; ENSP00000496832.1; ENSG00000187608.10 |
GeneIDi | 9636 |
KEGGi | hsa:9636 |
MANE-Selecti | ENST00000649529.1; ENSP00000496832.1; NM_005101.4; NP_005092.1 |
UCSCi | uc001acj.5, human |
Organism-specific databases
CTDi | 9636 |
DisGeNETi | 9636 |
GeneCardsi | ISG15 |
HGNCi | HGNC:4053, ISG15 |
HPAi | ENSG00000187608, Tissue enhanced (salivary) |
MalaCardsi | ISG15 |
MIMi | 147571, gene 616126, phenotype |
neXtProti | NX_P05161 |
OpenTargetsi | ENSG00000187608 |
Orphaneti | 319563, Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency |
PharmGKBi | PA28465 |
VEuPathDBi | HostDB:ENSG00000187608 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG0001, Eukaryota |
GeneTreei | ENSGT00940000162007 |
InParanoidi | P05161 |
OMAi | QCTVFMN |
OrthoDBi | 1367357at2759 |
PhylomeDBi | P05161 |
TreeFami | TF338379 |
Enzyme and pathway databases
PathwayCommonsi | P05161 |
Reactomei | R-HSA-1169408, ISG15 antiviral mechanism R-HSA-168276, NS1 Mediated Effects on Host Pathways R-HSA-168928, DDX58/IFIH1-mediated induction of interferon-alpha/beta R-HSA-5656169, Termination of translesion DNA synthesis R-HSA-909733, Interferon alpha/beta signaling R-HSA-936440, Negative regulators of DDX58/IFIH1 signaling |
SignaLinki | P05161 |
Miscellaneous databases
BioGRID-ORCSi | 9636, 25 hits in 1081 CRISPR screens |
ChiTaRSi | ISG15, human |
EvolutionaryTracei | P05161 |
GeneWikii | ISG15 |
GenomeRNAii | 9636 |
Pharosi | P05161, Tbio |
PROi | PR:P05161 |
RNActi | P05161, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000187608, Expressed in epithelium of bronchus and 240 other tissues |
ExpressionAtlasi | P05161, baseline and differential |
Genevisiblei | P05161, HS |
Family and domain databases
InterProi | View protein in InterPro IPR000626, Ubiquitin-like_dom IPR029071, Ubiquitin-like_domsf IPR019956, Ubiquitin_dom |
Pfami | View protein in Pfam PF00240, ubiquitin, 2 hits |
PRINTSi | PR00348, UBIQUITIN |
SMARTi | View protein in SMART SM00213, UBQ, 2 hits |
SUPFAMi | SSF54236, SSF54236, 2 hits |
PROSITEi | View protein in PROSITE PS50053, UBIQUITIN_2, 2 hits |
MobiDBi | Search... |
Entry informationi
Entry namei | ISG15_HUMAN | |
Accessioni | P05161Primary (citable) accession number: P05161 Secondary accession number(s): Q5SVA4, Q7Z2G2, Q96GF0 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | August 13, 1987 |
Last sequence update: | January 23, 2007 | |
Last modified: | May 25, 2022 | |
This is version 228 of the entry and version 5 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Direct protein sequencing, Reference proteomeDocuments
- Human chromosome 1
Human chromosome 1: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - Protein Spotlight
Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries