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Q64339 (ISG15_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 126. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
Gene names
Name:Isg15
Synonyms:G1p2, Ucrp
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length161 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

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. 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 SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, TRIM25, STAT5A, MAPK1/ERK2 and globin. Can also isgylate: DDX58/RIG-I which inhibits its function in antiviral signaling response and EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A and B virus, sindbis virus (SV) and herpes simplex type-1 (HHV-1). Plays a significant role in the control of neonatal Chikungunya virus (CHIKV) infection by acting as a putative immunomodulator of proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating the pathogenic cytokine response, often denoted as the cytokine storm. Plays a role in erythroid differentiation. 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. Ref.7 Ref.8 Ref.9 Ref.10 Ref.12 Ref.14 Ref.15 Ref.16

Subunit structure

Homodimer; disulfide-linked. Interacts with, and is conjugated to its targets by the UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme). Interacts with NEDD4 By similarity. Ref.11

Subcellular location

Cytoplasm. Secreted By similarity. Note: Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins By similarity.

Induction

By type I interferons.

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 By similarity.

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 By similarity.

Sequence similarities

Contains 2 ubiquitin-like domains.

Mass spectrometry

Molecular mass is 17015 Da from positions 2 - 155. Determined by MALDI. Ref.5

Ontologies

Keywords
   Biological processAntiviral defense
Ubl conjugation pathway
   Cellular componentCytoplasm
Secreted
   DomainRepeat
   PTMDisulfide bond
Isopeptide bond
S-nitrosylation
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processISG15-protein conjugation

Inferred from direct assay Ref.14. Source: UniProtKB

defense response to bacterium

Inferred from mutant phenotype Ref.16. Source: UniProtKB

defense response to virus

Inferred from mutant phenotype Ref.10. Source: UniProtKB

modification-dependent protein catabolic process

Inferred from direct assay PubMed 15485925. Source: MGI

negative regulation of protein ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of viral genome replication

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of erythrocyte differentiation

Inferred from mutant phenotype Ref.14. Source: UniProtKB

regulation of interferon-gamma production

Inferred from sequence or structural similarity. Source: UniProtKB

response to type I interferon

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

extracellular region

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionprotein binding

Inferred from physical interaction PubMed 24533902. Source: IntAct

protein tag

Inferred from direct assay PubMed 16139798. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Usp18Q9WTV62EBI-8345781,EBI-9119995

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 155154Ubiquitin-like protein ISG15
PRO_0000035988
Propeptide156 – 1616Removed in mature form By similarity
PRO_0000035989

Regions

Domain2 – 7675Ubiquitin-like 1
Domain77 – 15579Ubiquitin-like 2
Region151 – 1555Involved in the ligation of specific target proteins By similarity
Motif150 – 1556LRLRGG By similarity

Sites

Binding site1511Activating enzyme By similarity

Amino acid modifications

Modified residue761S-nitrosocysteine Ref.11
Modified residue1441S-nitrosocysteine Ref.11
Cross-link155Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins) By similarity

Experimental info

Sequence conflict111 – 1155QREQV → SGTS in CAA39939. Ref.1
Sequence conflict111 – 1155QREQV → SGTS in AAB02697. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q64339 [UniParc].

Last modified January 23, 2007. Version 4.
Checksum: 9C70D9A507979171

FASTA16117,898
        10         20         30         40         50         60 
MAWDLKVKML GGNDFLVSVT NSMTVSELKK QIAQKIGVPA FQQRLAHQTA VLQDGLTLSS 

        70         80         90        100        110        120 
LGLGPSSTVM LVVQNCSEPL SILVRNERGH SNIYEVFLTQ TVDTLKKKVS QREQVHEDQF 

       130        140        150        160 
WLSFEGRPME DKELLGEYGL KPQCTVIKHL RLRGGGGDQC A 

« Hide

References

« Hide 'large scale' references
[1]"Nucleotide sequence and deduced amino acid sequence of a cDNA encoding an interferon-induced mouse 15-KDa protein."
Fahey D.
Submitted (OCT-1992) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: BALB/c.
[2]"Sequence differences between murine ISG15, human ISG15 and ubiquitin: a functional divergence from ubiquitin."
Garlie N.K., Haas A.L., D'Cunha J., Schilling D., Knight E. Jr., Borden E.C.
Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Mammary gland.
[4]"Serpin 2a is induced in activated macrophages and conjugates to a ubiquitin homolog."
Hamerman J.A., Hayashi F., Schroeder L.A., Gygi S.P., Haas A.L., Hampson L., Coughlin P., Aebersold R., Aderem A.
J. Immunol. 168:2415-2423(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 9-30; 36-44 AND 89-106, CONJUGATION TO SERPINA3G.
[5]"Identification of a ubiquitin family protein as a novel neutrophil chemotactic factor."
Owhashi M., Taoka Y., Ishii K., Nakazawa S., Uemura H., Kambara H.
Biochem. Biophys. Res. Commun. 309:533-539(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PARTIAL PROTEIN SEQUENCE, CHEMOTACTIC ACTIVITY, MASS SPECTROMETRY.
[6]"High-throughput immunoblotting. Ubiquitin-like protein ISG15 modifies key regulators of signal transduction."
Malakhov M.P., Kim K.I., Malakhova O.A., Jacobs B.S., Borden E.C., Zhang D.-E.
J. Biol. Chem. 278:16608-16613(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: CONJUGATION TO JAK1; MAPK3 AND PLCG1.
[7]"Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo."
Lenschow D.J., Giannakopoulos N.V., Gunn L.J., Johnston C., O'Guin A.K., Schmidt R.E., Levine B., Virgin H.W. IV
J. Virol. 79:13974-13983(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SINDBIS VIRUS RESTRICTION.
[8]"Negative regulation of ISG15 E3 ligase EFP through its autoISGylation."
Zou W., Wang J., Zhang D.-E.
Biochem. Biophys. Res. Commun. 354:321-327(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN TRIM25 ISGYLATION.
[9]"ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP."
Okumura F., Zou W., Zhang D.E.
Genes Dev. 21:255-260(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN EIF4E2 ISGYLATION.
[10]"IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses."
Lenschow D.J., Lai C., Frias-Staheli N., Giannakopoulos N.V., Lutz A., Wolff T., Osiak A., Levine B., Schmidt R.E., Garcia-Sastre A., Leib D.A., Pekosz A., Knobeloch K.P., Horak I., Virgin H.W. IV
Proc. Natl. Acad. Sci. U.S.A. 104:1371-1376(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN HHV-1; SV; INFLUENZA A AND B VIRUS RESTRICTION.
[11]"Nitrosylation of ISG15 prevents the disulfide bond-mediated dimerization of ISG15 and contributes to effective ISGylation."
Okumura F., Lenschow D.J., Zhang D.E.
J. Biol. Chem. 283:24484-24488(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT, S-NITROSYLATION AT CYS-76 AND CYS-144.
[12]"Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation."
Kim M.J., Hwang S.Y., Imaizumi T., Yoo J.Y.
J. Virol. 82:1474-1483(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN DDX58 ISGYLATION.
[13]"Emerging role of ISG15 in antiviral immunity."
Skaug B., Chen Z.J.
Cell 143:187-190(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[14]"ISG15 modulates development of the erythroid lineage."
Maragno A.L., Pironin M., Alcalde H., Cong X., Knobeloch K.P., Tangy F., Zhang D.E., Ghysdael J., Quang C.T.
PLoS ONE 6:E26068-E26068(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN STAT5A; MAPK1; PLC-GAMMA AND GLOBIN ISGYLATION.
[15]"ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation."
Werneke S.W., Schilte C., Rohatgi A., Monte K.J., Michault A., Arenzana-Seisdedos F., Vanlandingham D.L., Higgs S., Fontanet A., Albert M.L., Lenschow D.J.
PLoS Pathog. 7:E1002322-E1002322(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[16]"Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency."
Bogunovic D., Byun M., Durfee L.A., Abhyankar A., Sanal O., Mansouri D., Salem S., Radovanovic I., Grant A.V., Adimi P., Mansouri N., Okada S., Bryant V.L., Kong X.F., Kreins A., Velez M.M., Boisson B., Khalilzadeh S. expand/collapse author list , Ozcelik U., Darazam I.A., Schoggins J.W., Rice C.M., Al-Muhsen S., Behr M., Vogt G., Puel A., Bustamante J., Gros P., Huibregtse J.M., Abel L., Boisson-Dupuis S., Casanova J.L.
Science 337:1684-1688(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X56602 mRNA. Translation: CAA39939.1.
U58202 Genomic DNA. Translation: AAB02697.1.
BC031424 mRNA. Translation: AAH31424.1.
BC083156 mRNA. Translation: AAH83156.1.
CCDSCCDS51405.1.
PIRS26434.
RefSeqNP_056598.2. NM_015783.3.
UniGeneMm.451527.
Mm.4950.

3D structure databases

ProteinModelPortalQ64339.
SMRQ64339. Positions 3-154.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid782389. 3 interactions.
IntActQ64339. 6 interactions.
MINTMINT-4139466.

PTM databases

PhosphoSiteQ64339.

Proteomic databases

MaxQBQ64339.
PaxDbQ64339.
PRIDEQ64339.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000085425; ENSMUSP00000082548; ENSMUSG00000035692.
GeneID100038882.
KEGGmmu:100038882.
UCSCuc012dri.1. mouse.

Organism-specific databases

CTD9636.
MGIMGI:1855694. Isg15.

Phylogenomic databases

eggNOGCOG5272.
GeneTreeENSGT00750000117818.
HOGENOMHOG000233942.
HOVERGENHBG000057.
InParanoidQ64339.
KOK12159.
OMAFWLTFEG.
OrthoDBEOG7B05FG.
PhylomeDBQ64339.
TreeFamTF338379.

Gene expression databases

ArrayExpressQ64339.
BgeeQ64339.
CleanExMM_ISG15.
GenevestigatorQ64339.

Family and domain databases

InterProIPR000626. Ubiquitin-like.
IPR029071. Ubiquitin-rel_dom.
[Graphical view]
PfamPF00240. ubiquitin. 2 hits.
[Graphical view]
SMARTSM00213. UBQ. 2 hits.
[Graphical view]
SUPFAMSSF54236. SSF54236. 2 hits.
PROSITEPS50053. UBIQUITIN_2. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

NextBio445160.
PROQ64339.
SOURCESearch...

Entry information

Entry nameISG15_MOUSE
AccessionPrimary (citable) accession number: Q64339
Secondary accession number(s): Q8K0H3
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 23, 2007
Last modified: July 9, 2014
This is version 126 of the entry and version 4 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot