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Q64339

- ISG15_MOUSE

UniProt

Q64339 - ISG15_MOUSE

Protein

Ubiquitin-like protein ISG15

Gene

Isg15

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
  1. 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 enzymeBy similarity

    GO - Molecular functioni

    1. protein binding Source: IntAct
    2. protein tag Source: MGI

    GO - Biological processi

    1. defense response to bacterium Source: UniProtKB
    2. defense response to virus Source: UniProtKB
    3. ISG15-protein conjugation 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

    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

    Keywords - Cellular componenti

    Cytoplasm, Secreted

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 155154Ubiquitin-like protein ISG15PRO_0000035988Add
    BLAST
    Propeptidei156 – 1616Removed in mature formBy similarityPRO_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)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 By similarity.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.By similarity

    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.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

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

    Region

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

    Motif

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

    Sequence similaritiesi

    Contains 2 ubiquitin-like domains.PROSITE-ProRule annotation

    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

    Experimental Info

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

    Mass spectrometryi

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

    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: October 1, 2014
    This is version 128 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