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Protein

Ubiquitin-like protein ISG15

Gene

ISG15

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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)DescriptionActionsGraphical viewLength
Binding sitei153Activating enzymeBy similarity1

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 bone mineralization 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

Keywordsi

Biological processAntiviral 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 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

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

EuPathDBiHostDB:ENSG00000187608.8
HGNCiHGNC:4053 ISG15
MIMi147571 gene
neXtProtiNX_P05161

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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

DisGeNETi9636
MalaCardsiISG15
MIMi616126 phenotype
OpenTargetsiENSG00000187608
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)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved1 Publication
ChainiPRO_00000359862 – 157Ubiquitin-like protein ISG15Add BLAST156
PropeptideiPRO_0000035987158 – 165Removed in mature form8

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei78S-nitrosocysteine; alternate1 Publication1
Disulfide bondi78Interchain (with C-87 in UBE2N); alternate1 Publication
Cross-linki157Glycyl 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
PhosphoSitePlusiP05161

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). Interacts with NEDD4.Curated3 Publications
(Microbial infection) Interacts with vaccinia virus protein E3.1 Publication
(Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.1 Publication

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi114995, 187 interactors
DIPiDIP-29814N
IntActiP05161, 41 interactors
MINTiP05161
STRINGi9606.ENSP00000368699

Structurei

Secondary structure

1165
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi4 – 9Combined sources6
Beta strandi14 – 18Combined sources5
Helixi25 – 36Combined sources12
Helixi40 – 42Combined sources3
Beta strandi43 – 48Combined sources6
Beta strandi56 – 58Combined sources3
Helixi60 – 63Combined sources4
Beta strandi70 – 75Combined sources6
Beta strandi82 – 87Combined sources6
Beta strandi93 – 98Combined sources6
Helixi104 – 115Combined sources12
Helixi119 – 121Combined sources3
Beta strandi122 – 126Combined sources5
Beta strandi129 – 131Combined sources3
Helixi137 – 140Combined sources4
Beta strandi147 – 152Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
5TL6X-ray2.62A/C80-157[»]
5W8TX-ray2.76B/D80-156[»]
5W8UX-ray2.41B/D80-156[»]
6FFAX-ray1.50B79-155[»]
ProteinModelPortaliP05161
SMRiP05161
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP05161

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini2 – 78Ubiquitin-like 1PROSITE-ProRule annotationAdd BLAST77
Domaini79 – 157Ubiquitin-like 2PROSITE-ProRule annotationAdd BLAST79

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni153 – 157Involved in the ligation of specific target proteinsBy similarity5

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi152 – 157LRLRGG6

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

Keywords - Domaini

Repeat

Phylogenomic databases

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

Family and domain databases

InterProiView protein in InterPro
IPR019956 Ubiquitin
IPR029071 Ubiquitin-like_domsf
IPR000626 Ubiquitin_dom
PfamiView protein in Pfam
PF00240 ubiquitin, 2 hits
PRINTSiPR00348 UBIQUITIN
SMARTiView protein in SMART
SM00213 UBQ, 2 hits
SUPFAMiSSF54236 SSF54236, 2 hits
PROSITEiView protein in PROSITE
PS50053 UBIQUITIN_2, 2 hits

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)DescriptionActionsGraphical viewLength
Sequence conflicti35K → N in AAA36128 (PubMed:3476954).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01618183S → 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
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

Similar proteinsi

Entry informationi

Entry nameiISG15_HUMAN
AccessioniPrimary (citable) accession number: P05161
Secondary accession number(s): Q5SVA4, Q7Z2G2, Q96GF0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: January 23, 2007
Last modified: May 23, 2018
This is version 202 of the entry and version 5 of the sequence. See 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

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