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Protein

Ubiquitin-like protein ISG15

Gene

ISG15

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. 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 therby 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.19 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei153 – 1531Activating enzymeBy similarity

GO - Molecular functioni

GO - Biological processi

  • defense response to bacterium Source: UniProtKB
  • defense response to virus Source: UniProtKB
  • ISG15-protein conjugation Source: UniProtKB
  • modification-dependent protein catabolic process Source: Ensembl
  • negative regulation of protein ubiquitination Source: UniProtKB
  • negative regulation of type I interferon production Source: Reactome
  • negative regulation of viral genome replication Source: UniProtKB
  • positive regulation of erythrocyte differentiation Source: Ensembl
  • regulation of interferon-gamma production Source: UniProtKB
  • response to type I interferon Source: UniProtKB
  • translesion synthesis Source: Reactome
  • type I interferon signaling pathway Source: Reactome
  • viral process Source: UniProtKB-KW
Complete GO annotation...

Keywords - Biological processi

Antiviral defense, Host-virus interaction, Immunity, Innate immunity, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-1169408. ISG15 antiviral mechanism.
R-HSA-168276. NS1 Mediated Effects on Host Pathways.
R-HSA-168928. RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways.
R-HSA-5656169. Termination of translesion DNA synthesis.
R-HSA-909733. Interferon alpha/beta signaling.
R-HSA-936440. Negative regulators of RIG-I/MDA5 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin-like protein ISG15
Alternative name(s):
Interferon-induced 15 kDa protein
Interferon-induced 17 kDa protein
Short name:
IP17
Ubiquitin cross-reactive protein
Short name:
hUCRP
Gene namesi
Name:ISG15
Synonyms:G1P2, UCRP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:4053. ISG15.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: Reactome
  • extracellular region Source: UniProtKB
  • nucleoplasm Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Secreted

Pathology & Biotechi

Involvement in diseasei

Immunodeficiency 38, with basal ganglia calcification (IMD38)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease 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 tubercolosis infections. Affected individuals have intracranial calcification.
See also OMIM:616126

Organism-specific databases

MalaCardsiISG15.
MIMi616126. phenotype.
Orphaneti319563. Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency.
PharmGKBiPA28465.

Polymorphism and mutation databases

BioMutaiISG15.
DMDMi52001470.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemoved1 Publication
Chaini2 – 157156Ubiquitin-like protein ISG15PRO_0000035986Add
BLAST
Propeptidei158 – 1658Removed in mature formPRO_0000035987

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei78 – 781S-nitrosocysteine; alternate1 Publication
Disulfide bondi78 – 78Interchain (with C-87 in UBE2N); alternate1 Publication
Cross-linki157 – 157Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins)PROSITE-ProRule annotation

Post-translational modificationi

S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.1 Publication
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.2 Publications

Keywords - PTMi

Disulfide bond, Isopeptide bond, S-nitrosylation

Proteomic databases

EPDiP05161.
MaxQBiP05161.
PaxDbiP05161.
PeptideAtlasiP05161.
PRIDEiP05161.
TopDownProteomicsiP05161.

PTM databases

iPTMnetiP05161.
PhosphoSiteiP05161.

Expressioni

Tissue specificityi

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.2 Publications

Inductioni

Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses.1 Publication

Gene expression databases

BgeeiENSG00000187608.
CleanExiHS_ISG15.
ExpressionAtlasiP05161. baseline and differential.
GenevisibleiP05161. HS.

Organism-specific databases

HPAiHPA004627.

Interactioni

Subunit structurei

Homodimer; disulfide-linked. Interacts with, and is conjugated to its targets by the UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (Probable). Interaction with influenza B NS1 protein inhibits its conjugation. Interacts with NEDD4.Curated4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
FLNBO753694EBI-746466,EBI-352089
PPM1BO756882EBI-746466,EBI-1047039
UBA7P412266EBI-746466,EBI-751921
USP18Q9UMW84EBI-746466,EBI-356206

Protein-protein interaction databases

BioGridi114995. 194 interactions.
DIPiDIP-29814N.
IntActiP05161. 7 interactions.
MINTiMINT-1440156.
STRINGi9606.ENSP00000368699.

Structurei

Secondary structure

1
165
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi4 – 96Combined sources
Beta strandi14 – 185Combined sources
Helixi25 – 3612Combined sources
Helixi40 – 423Combined sources
Beta strandi43 – 486Combined sources
Beta strandi56 – 583Combined sources
Helixi60 – 634Combined sources
Beta strandi70 – 756Combined sources
Beta strandi82 – 876Combined sources
Beta strandi93 – 986Combined sources
Helixi104 – 11512Combined sources
Helixi119 – 1213Combined sources
Beta strandi122 – 1265Combined sources
Helixi137 – 1404Combined sources
Beta strandi147 – 1526Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1Z2MX-ray2.50A1-155[»]
2HJ8NMR-A79-157[»]
3PHXX-ray1.60B79-156[»]
3PSEX-ray2.30B1-156[»]
3R66X-ray2.30C/D1-157[»]
3RT3X-ray2.01B1-158[»]
3SDLX-ray2.29C/D1-157[»]
ProteinModelPortaliP05161.
SMRiP05161. Positions 4-154.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP05161.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini2 – 7877Ubiquitin-like 1PROSITE-ProRule annotationAdd
BLAST
Domaini79 – 15779Ubiquitin-like 2PROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni153 – 1575Involved in the ligation of specific target proteinsBy similarity

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi152 – 1576LRLRGG

Domaini

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).1 Publication

Sequence similaritiesi

Contains 2 ubiquitin-like domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0001. Eukaryota.
COG5272. LUCA.
GeneTreeiENSGT00810000125435.
HOGENOMiHOG000233942.
HOVERGENiHBG000057.
InParanoidiP05161.
KOiK12159.
OMAiFWLTFEG.
OrthoDBiEOG091G178I.
PhylomeDBiP05161.
TreeFamiTF338379.

Family and domain databases

InterProiIPR019956. Ubiquitin.
IPR029071. Ubiquitin-rel_dom.
IPR000626. Ubiquitin_dom.
[Graphical view]
PfamiPF00240. ubiquitin. 2 hits.
[Graphical view]
PRINTSiPR00348. UBIQUITIN.
SMARTiSM00213. UBQ. 2 hits.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 2 hits.
PROSITEiPS50053. UBIQUITIN_2. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P05161-1 [UniParc]FASTAAdd to basket

« Hide

        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
Length:165
Mass (Da):17,888
Last modified:January 23, 2007 - v5
Checksum:iB6858A15AB0FFFDE
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti35 – 351K → N in AAA36128 (PubMed:3476954).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti83 – 831S → N.3 Publications
Corresponds to variant rs1921 [ dbSNP | Ensembl ].
VAR_016181

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. Translation: CAI15574.1.
CH471183 Genomic DNA. Translation: EAW56295.1.
BC009507 mRNA. Translation: AAH09507.1.
CCDSiCCDS6.1.
PIRiA28304. A28138.
RefSeqiNP_005092.1. NM_005101.3.
UniGeneiHs.458485.

Genome annotation databases

EnsembliENST00000379389; ENSP00000368699; ENSG00000187608.
GeneIDi9636.
KEGGihsa:9636.
UCSCiuc001acj.5. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

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. Translation: CAI15574.1.
CH471183 Genomic DNA. Translation: EAW56295.1.
BC009507 mRNA. Translation: AAH09507.1.
CCDSiCCDS6.1.
PIRiA28304. A28138.
RefSeqiNP_005092.1. NM_005101.3.
UniGeneiHs.458485.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1Z2MX-ray2.50A1-155[»]
2HJ8NMR-A79-157[»]
3PHXX-ray1.60B79-156[»]
3PSEX-ray2.30B1-156[»]
3R66X-ray2.30C/D1-157[»]
3RT3X-ray2.01B1-158[»]
3SDLX-ray2.29C/D1-157[»]
ProteinModelPortaliP05161.
SMRiP05161. Positions 4-154.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114995. 194 interactions.
DIPiDIP-29814N.
IntActiP05161. 7 interactions.
MINTiMINT-1440156.
STRINGi9606.ENSP00000368699.

PTM databases

iPTMnetiP05161.
PhosphoSiteiP05161.

Polymorphism and mutation databases

BioMutaiISG15.
DMDMi52001470.

Proteomic databases

EPDiP05161.
MaxQBiP05161.
PaxDbiP05161.
PeptideAtlasiP05161.
PRIDEiP05161.
TopDownProteomicsiP05161.

Protocols and materials databases

DNASUi9636.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000379389; ENSP00000368699; ENSG00000187608.
GeneIDi9636.
KEGGihsa:9636.
UCSCiuc001acj.5. human.

Organism-specific databases

CTDi9636.
GeneCardsiISG15.
HGNCiHGNC:4053. ISG15.
HPAiHPA004627.
MalaCardsiISG15.
MIMi147571. gene.
616126. phenotype.
neXtProtiNX_P05161.
Orphaneti319563. Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency.
PharmGKBiPA28465.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0001. Eukaryota.
COG5272. LUCA.
GeneTreeiENSGT00810000125435.
HOGENOMiHOG000233942.
HOVERGENiHBG000057.
InParanoidiP05161.
KOiK12159.
OMAiFWLTFEG.
OrthoDBiEOG091G178I.
PhylomeDBiP05161.
TreeFamiTF338379.

Enzyme and pathway databases

ReactomeiR-HSA-1169408. ISG15 antiviral mechanism.
R-HSA-168276. NS1 Mediated Effects on Host Pathways.
R-HSA-168928. RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways.
R-HSA-5656169. Termination of translesion DNA synthesis.
R-HSA-909733. Interferon alpha/beta signaling.
R-HSA-936440. Negative regulators of RIG-I/MDA5 signaling.

Miscellaneous databases

EvolutionaryTraceiP05161.
GeneWikiiISG15.
GenomeRNAii9636.
PROiP05161.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000187608.
CleanExiHS_ISG15.
ExpressionAtlasiP05161. baseline and differential.
GenevisibleiP05161. HS.

Family and domain databases

InterProiIPR019956. Ubiquitin.
IPR029071. Ubiquitin-rel_dom.
IPR000626. Ubiquitin_dom.
[Graphical view]
PfamiPF00240. ubiquitin. 2 hits.
[Graphical view]
PRINTSiPR00348. UBIQUITIN.
SMARTiSM00213. UBQ. 2 hits.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 2 hits.
PROSITEiPS50053. UBIQUITIN_2. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiISG15_HUMAN
AccessioniPrimary (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: September 7, 2016
This is version 185 of the entry and version 5 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.