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Q64339

- ISG15_MOUSE

UniProt

Q64339 - ISG15_MOUSE

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Protein
Ubiquitin-like protein ISG15
Gene
Isg15, G1p2, Ucrp
Organism
Mus musculus (Mouse)
Status
Reviewed - 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 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.8 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei151 – 1511Activating enzyme By similarity

GO - Molecular functioni

  1. protein binding Source: IntAct
  2. protein tag Source: MGI
Complete GO annotation...

GO - Biological processi

  1. ISG15-protein conjugation Source: UniProtKB
  2. defense response to bacterium Source: UniProtKB
  3. defense response to virus Source: UniProtKB
  4. modification-dependent protein catabolic process Source: MGI
  5. negative regulation of protein ubiquitination Source: UniProtKB
  6. negative regulation of viral genome replication Source: UniProtKB
  7. positive regulation of erythrocyte differentiation Source: UniProtKB
  8. regulation of interferon-gamma production Source: UniProtKB
  9. response to type I interferon Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Antiviral defense, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiREACT_198533. ISG15 antiviral mechanism.

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
Gene namesi
Name:Isg15
Synonyms:G1p2, Ucrp
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 4

Organism-specific databases

MGIiMGI:1855694. Isg15.

Subcellular locationi

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.

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB-SubCell
  2. extracellular region Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Secreted

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed By similarity
Chaini2 – 155154Ubiquitin-like protein ISG15
PRO_0000035988Add
BLAST
Propeptidei156 – 1616Removed in mature form By similarity
PRO_0000035989

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei76 – 761S-nitrosocysteine1 Publication
Modified residuei144 – 1441S-nitrosocysteine1 Publication
Cross-linki155 – 155Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins) By similarity

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.
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.

Keywords - PTMi

Disulfide bond, Isopeptide bond, S-nitrosylation

Proteomic databases

MaxQBiQ64339.
PaxDbiQ64339.
PRIDEiQ64339.

PTM databases

PhosphoSiteiQ64339.

Expressioni

Inductioni

By type I interferons.

Gene expression databases

ArrayExpressiQ64339.
BgeeiQ64339.
CleanExiMM_ISG15.
GenevestigatoriQ64339.

Interactioni

Subunit structurei

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.1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
Usp18Q9WTV62EBI-8345781,EBI-9119995

Protein-protein interaction databases

BioGridi782389. 3 interactions.
IntActiQ64339. 6 interactions.
MINTiMINT-4139466.

Structurei

3D structure databases

ProteinModelPortaliQ64339.
SMRiQ64339. Positions 3-154.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini2 – 7675Ubiquitin-like 1
Add
BLAST
Domaini77 – 15579Ubiquitin-like 2
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni151 – 1555Involved in the ligation of specific target proteins By similarity

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi150 – 1556LRLRGG By similarity

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 By similarity.

Sequence similaritiesi

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiCOG5272.
GeneTreeiENSGT00750000117818.
HOGENOMiHOG000233942.
HOVERGENiHBG000057.
InParanoidiQ64339.
KOiK12159.
OMAiFWLTFEG.
OrthoDBiEOG7B05FG.
PhylomeDBiQ64339.
TreeFamiTF338379.

Family and domain databases

InterProiIPR000626. Ubiquitin-like.
IPR029071. Ubiquitin-rel_dom.
[Graphical view]
PfamiPF00240. ubiquitin. 2 hits.
[Graphical view]
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.

Q64339-1 [UniParc]FASTAAdd to Basket

« Hide

MAWDLKVKML GGNDFLVSVT NSMTVSELKK QIAQKIGVPA FQQRLAHQTA    50
VLQDGLTLSS LGLGPSSTVM LVVQNCSEPL SILVRNERGH SNIYEVFLTQ 100
TVDTLKKKVS QREQVHEDQF WLSFEGRPME DKELLGEYGL KPQCTVIKHL 150
RLRGGGGDQC A 161
Length:161
Mass (Da):17,898
Last modified:January 23, 2007 - v4
Checksum:i9C70D9A507979171
GO

Mass spectrometryi

Molecular mass is 17015 Da from positions 2 - 155. Determined by MALDI. 1 Publication

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti111 – 1155QREQV → SGTS in CAA39939. 1 Publication
Sequence conflicti111 – 1155QREQV → SGTS in AAB02697. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X56602 mRNA. Translation: CAA39939.1.
U58202 Genomic DNA. Translation: AAB02697.1.
BC031424 mRNA. Translation: AAH31424.1.
BC083156 mRNA. Translation: AAH83156.1.
CCDSiCCDS51405.1.
PIRiS26434.
RefSeqiNP_056598.2. NM_015783.3.
UniGeneiMm.451527.
Mm.4950.

Genome annotation databases

EnsembliENSMUST00000085425; ENSMUSP00000082548; ENSMUSG00000035692.
GeneIDi100038882.
KEGGimmu:100038882.
UCSCiuc012dri.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X56602 mRNA. Translation: CAA39939.1 .
U58202 Genomic DNA. Translation: AAB02697.1 .
BC031424 mRNA. Translation: AAH31424.1 .
BC083156 mRNA. Translation: AAH83156.1 .
CCDSi CCDS51405.1.
PIRi S26434.
RefSeqi NP_056598.2. NM_015783.3.
UniGenei Mm.451527.
Mm.4950.

3D structure databases

ProteinModelPortali Q64339.
SMRi Q64339. Positions 3-154.
ModBasei Search...

Protein-protein interaction databases

BioGridi 782389. 3 interactions.
IntActi Q64339. 6 interactions.
MINTi MINT-4139466.

PTM databases

PhosphoSitei Q64339.

Proteomic databases

MaxQBi Q64339.
PaxDbi Q64339.
PRIDEi Q64339.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000085425 ; ENSMUSP00000082548 ; ENSMUSG00000035692 .
GeneIDi 100038882.
KEGGi mmu:100038882.
UCSCi uc012dri.1. mouse.

Organism-specific databases

CTDi 9636.
MGIi MGI:1855694. Isg15.

Phylogenomic databases

eggNOGi COG5272.
GeneTreei ENSGT00750000117818.
HOGENOMi HOG000233942.
HOVERGENi HBG000057.
InParanoidi Q64339.
KOi K12159.
OMAi FWLTFEG.
OrthoDBi EOG7B05FG.
PhylomeDBi Q64339.
TreeFami TF338379.

Enzyme and pathway databases

Reactomei REACT_198533. ISG15 antiviral mechanism.

Miscellaneous databases

NextBioi 445160.
PROi Q64339.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q64339.
Bgeei Q64339.
CleanExi MM_ISG15.
Genevestigatori Q64339.

Family and domain databases

InterProi IPR000626. Ubiquitin-like.
IPR029071. Ubiquitin-rel_dom.
[Graphical view ]
Pfami PF00240. ubiquitin. 2 hits.
[Graphical view ]
SMARTi SM00213. UBQ. 2 hits.
[Graphical view ]
SUPFAMi SSF54236. SSF54236. 2 hits.
PROSITEi PS50053. UBIQUITIN_2. 2 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. 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. 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. Cited for: FUNCTION.

Entry informationi

Entry nameiISG15_MOUSE
AccessioniPrimary (citable) accession number: Q64339
Secondary accession number(s): Q8K0H3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 23, 2007
Last modified: September 3, 2014
This is version 127 of the entry and version 4 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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