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Ubiquitin-like protein ISG15 (Interferon-induced 15 kDa protein) (Interferon-induced 17 kDa protein) (IP17) (Ubiquitin cross-reactive protein) (hUCRP)

 ISG15_HUMAN             Reviewed;         165 AA.
P05161; Q5SVA4; Q7Z2G2; Q96GF0;
13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
23-JAN-2007, sequence version 5.
25-APR-2018, entry version 201.
RecName: Full=Ubiquitin-like protein ISG15;
AltName: Full=Interferon-induced 15 kDa protein;
AltName: Full=Interferon-induced 17 kDa protein;
Short=IP17;
AltName: Full=Ubiquitin cross-reactive protein;
Short=hUCRP;
Flags: Precursor;
Name=ISG15; Synonyms=G1P2, UCRP;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=3087979;
Blomstrom D.C., Fahey D., Kutny R., Korant B.D., Knight E. Jr.;
"Molecular characterization of the interferon-induced 15-kDa protein.
Molecular cloning and nucleotide and amino acid sequence.";
J. Biol. Chem. 261:8811-8816(1986).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=3476954; DOI=10.1073/pnas.84.18.6394;
Reich N., Evans B., Levy D., Fahey D., Knight E. Jr.,
Darnell J.E. Jr.;
"Interferon-induced transcription of a gene encoding a 15-kDa protein
depends on an upstream enhancer element.";
Proc. Natl. Acad. Sci. U.S.A. 84:6394-6398(1987).
[3]
NUCLEOTIDE SEQUENCE [MRNA], AND PROTEOLYTIC PROCESSING.
PubMed=3350799;
Knight E. Jr., Fahey D., Cordova B., Hillman M. Jr., Kutny R.,
Reich N., Blomstrom D.C.;
"A 15-kDa interferon-induced protein is derived by COOH-terminal
processing of a 17-kDa precursor.";
J. Biol. Chem. 263:4520-4522(1988).
[4]
ERRATUM.
Knight E. Jr., Fahey D., Cordova B., Hillman M. Jr., Kutny R.,
Reich N., Blomstrom D.C.;
J. Biol. Chem. 263:10040-10040(1988).
[5]
NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASN-83.
TISSUE=Testis;
Kamitani T., Fukuda-Kamitani T.;
"Conjugation by ubiquitin-like proteins.";
Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-83.
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
Phelan M., Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor
vector.";
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=16710414; DOI=10.1038/nature04727;
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
Beck S., Rogers J., Bentley D.R.;
"The DNA sequence and biological annotation of human chromosome 1.";
Nature 441:315-321(2006).
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-83.
TISSUE=Colon;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[10]
PROTEIN SEQUENCE OF 2-38 AND 151-165, AND PROTEOLYTIC PROCESSING.
PubMed=2477469; DOI=10.1089/jir.1989.9.493;
Feltham N., Hillman M. Jr., Cordova B., Fahey D., Larsen B.,
Blomstrom D.C., Knight E. Jr.;
"A 15-kD interferon-induced protein and its 17-kD precursor:
expression in Escherichia coli, purification, and characterization.";
J. Interferon Res. 9:493-507(1989).
[11]
SIMILARITY TO UBIQUITIN.
PubMed=2440890;
Haas A.L., Ahrens P., Bright P.M., Ankel H.;
"Interferon induces a 15-kilodalton protein exhibiting marked homology
to ubiquitin.";
J. Biol. Chem. 262:11315-11323(1987).
[12]
FUNCTION.
PubMed=1373138;
Loeb K.R., Haas A.L.;
"The interferon-inducible 15-kDa ubiquitin homolog conjugates to
intracellular proteins.";
J. Biol. Chem. 267:7806-7813(1992).
[13]
FUNCTION.
PubMed=7526157; DOI=10.1128/MCB.14.12.8408;
Loeb K.R., Haas A.L.;
"Conjugates of ubiquitin cross-reactive protein distribute in a
cytoskeletal pattern.";
Mol. Cell. Biol. 14:8408-8419(1994).
[14]
FUNCTION.
PubMed=8550581; DOI=10.1074/jbc.271.1.324;
Narasimhan J., Potter J.L., Haas A.L.;
"Conjugation of the 15-kDa interferon-induced ubiquitin homolog is
distinct from that of ubiquitin.";
J. Biol. Chem. 271:324-330(1996).
[15]
FUNCTION.
PubMed=2005397;
Knight E. Jr., Cordova B.;
"IFN-induced 15-kDa protein is released from human lymphocytes and
monocytes.";
J. Immunol. 146:2280-2284(1991).
[16]
TISSUE SPECIFICITY.
PubMed=7490683; DOI=10.1002/path.1711770210;
Lowe J., McDermott H., Loeb K., Landon M., Haas A.L., Mayer R.J.;
"Immunohistochemical localization of ubiquitin cross-reactive protein
in human tissues.";
J. Pathol. 177:163-169(1995).
[17]
INTERACTION WITH UBE1L AND INFLUENZA B NS1.
PubMed=11157743; DOI=10.1093/emboj/20.3.362;
Yuan W., Krug R.M.;
"Influenza B virus NS1 protein inhibits conjugation of the interferon
(IFN)-induced ubiquitin-like ISG15 protein.";
EMBO J. 20:362-371(2001).
[18]
CHARACTERIZATION.
PubMed=11788588; DOI=10.1074/jbc.M109078200;
Malakhov M.P., Malakhova O.A., Kim K.I., Ritchie K.J., Zhang D.-E.;
"UBP43 (USP18) specifically removes ISG15 from conjugated proteins.";
J. Biol. Chem. 277:9976-9981(2002).
[19]
INTERACTION WITH UBE2E2.
PubMed=15131269; DOI=10.1073/pnas.0402528101;
Zhao C., Beaudenon S.L., Kelley M.L., Waddell M.B., Yuan W.,
Schulman B.A., Huibregtse J.M., Krug R.M.;
"The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an
IFN-alpha/beta-induced ubiquitin-like protein.";
Proc. Natl. Acad. Sci. U.S.A. 101:7578-7582(2004).
[20]
FUNCTION IN UBE2N ISGYLATION.
PubMed=16112642; DOI=10.1016/j.bbrc.2005.08.034;
Takeuchi T., Yokosawa H.;
"ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating
activity.";
Biochem. Biophys. Res. Commun. 336:9-13(2005).
[21]
FUNCTION IN UBE2E1 AND UBE2L6 ISGYLATION.
PubMed=16428300; DOI=10.1093/jb/mvi172;
Takeuchi T., Iwahara S., Saeki Y., Sasajima H., Yokosawa H.;
"Link between the ubiquitin conjugation system and the ISG15
conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2
enzyme.";
J. Biochem. 138:711-719(2005).
[22]
FUNCTION IN IFIT1; DDX58 AND MX1 ISGYLATION.
PubMed=16009940; DOI=10.1073/pnas.0504754102;
Zhao C., Denison C., Huibregtse J.M., Gygi S.P., Krug R.M.;
"Human ISG15 conjugation targets both IFN-induced and constitutively
expressed proteins functioning in diverse cellular pathways.";
Proc. Natl. Acad. Sci. U.S.A. 102:10200-10205(2005).
[23]
FUNCTION IN PPM1B ISGYLATION.
PubMed=16872604; DOI=10.1016/j.febslet.2006.07.032;
Takeuchi T., Kobayashi T., Tamura S., Yokosawa H.;
"Negative regulation of protein phosphatase 2Cbeta by ISG15
conjugation.";
FEBS Lett. 580:4521-4526(2006).
[24]
FUNCTION IN HIV-1 RESTRICTION.
PubMed=16434471; DOI=10.1073/pnas.0510518103;
Okumura A., Lu G., Pitha-Rowe I., Pitha P.M.;
"Innate antiviral response targets HIV-1 release by the induction of
ubiquitin-like protein ISG15.";
Proc. Natl. Acad. Sci. U.S.A. 103:1440-1445(2006).
[25]
DOMAINS UBIQUITIN-LIKE 1 AND 2.
PubMed=18356159; DOI=10.1074/jbc.M800162200;
Chang Y.G., Yan X.Z., Xie Y.Y., Gao X.C., Song A.X., Zhang D.E.,
Hu H.Y.;
"Different roles for two ubiquitin-like domains of ISG15 in protein
modification.";
J. Biol. Chem. 283:13370-13377(2008).
[26]
S-NITROSYLATION AT CYS-78.
PubMed=18606809; DOI=10.1074/jbc.M803795200;
Okumura F., Lenschow D.J., Zhang D.E.;
"Nitrosylation of ISG15 prevents the disulfide bond-mediated
dimerization of ISG15 and contributes to effective ISGylation.";
J. Biol. Chem. 283:24484-24488(2008).
[27]
FUNCTION IN EBOLA VIRUS RESTRICTION, AND INTERACTION WITH NEDD4.
PubMed=18305167; DOI=10.1073/pnas.0710629105;
Okumura A., Pitha P.M., Harty R.N.;
"ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner
by blocking Nedd4 ligase activity.";
Proc. Natl. Acad. Sci. U.S.A. 105:3974-3979(2008).
[28]
FUNCTION IN FLNB ISGYLATION.
PubMed=19270716; DOI=10.1038/embor.2009.23;
Jeon Y.J., Choi J.S., Lee J.Y., Yu K.R., Kim S.M., Ka S.H., Oh K.H.,
Kim K.I., Zhang D.E., Bang O.S., Chung C.H.;
"ISG15 modification of filamin B negatively regulates the type I
interferon-induced JNK signalling pathway.";
EMBO Rep. 10:374-380(2009).
[29]
REVIEW.
PubMed=19680460; DOI=10.1159/000226245;
Harty R.N., Pitha P.M., Okumura A.;
"Antiviral activity of innate immune protein ISG15.";
J. Innate Immun. 1:397-404(2009).
[30]
FUNCTION IN INFLUENZA A VIRUS RESTRICTION.
PubMed=19357168; DOI=10.1128/JVI.01667-08;
Hsiang T.Y., Zhao C., Krug R.M.;
"Interferon-induced ISG15 conjugation inhibits influenza A virus gene
expression and replication in human cells.";
J. Virol. 83:5971-5977(2009).
[31]
REVIEW.
PubMed=20153823; DOI=10.1016/j.bbadis.2010.02.006;
Jeon Y.J., Yoo H.M., Chung C.H.;
"ISG15 and immune diseases.";
Biochim. Biophys. Acta 1802:485-496(2010).
[32]
REVIEW.
PubMed=20946978; DOI=10.1016/j.cell.2010.09.033;
Skaug B., Chen Z.J.;
"Emerging role of ISG15 in antiviral immunity.";
Cell 143:187-190(2010).
[33]
FUNCTION.
PubMed=20639253; DOI=10.1136/gut.2009.195545;
Broering R., Zhang X., Kottilil S., Trippler M., Jiang M., Lu M.,
Gerken G., Schlaak J.F.;
"The interferon stimulated gene 15 functions as a proviral factor for
the hepatitis C virus and as a regulator of the IFN response.";
Gut 59:1111-1119(2010).
[34]
FUNCTION IN IRF3 ISGYLATION.
PubMed=20308324; DOI=10.1128/MCB.01466-09;
Shi H.X., Yang K., Liu X., Liu X.Y., Wei B., Shan Y.F., Zhu L.H.,
Wang C.;
"Positive regulation of interferon regulatory factor 3 activation by
Herc5 via ISG15 modification.";
Mol. Cell. Biol. 30:2424-2436(2010).
[35]
FUNCTION IN INFLUENZA A VIRUS NS1 ISGYLATION.
PubMed=20133869; DOI=10.1073/pnas.0909144107;
Zhao C., Hsiang T.Y., Kuo R.L., Krug R.M.;
"ISG15 conjugation system targets the viral NS1 protein in influenza A
virus-infected cells.";
Proc. Natl. Acad. Sci. U.S.A. 107:2253-2258(2010).
[36]
REVIEW.
PubMed=21994614; DOI=10.3390/v2102154;
Lenschow D.J.;
"Antiviral properties of ISG15.";
Viruses 2:2154-2168(2010).
[37]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[38]
REVIEW.
PubMed=21190487; DOI=10.1089/jir.2010.0110;
Zhang D., Zhang D.E.;
"Interferon-stimulated gene 15 and the protein ISGylation system.";
J. Interferon Cytokine Res. 31:119-130(2011).
[39]
FUNCTION IN CHMP5; CHMP2A; CHMP4B AND CHMP6 ISGYLATION.
PubMed=21543490; DOI=10.1128/JVI.02610-10;
Kuang Z., Seo E.J., Leis J.;
"Mechanism of inhibition of retrovirus release from cells by
interferon-induced gene ISG15.";
J. Virol. 85:7153-7161(2011).
[40]
REVIEW.
PubMed=22666250; DOI=10.1155/2012/532723;
Seo E.J., Leis J.;
"Budding of enveloped viruses: interferon-induced ISG15-antivirus
mechanisms targeting the release process.";
Adv. Virol. 2012:532723-532723(2012).
[41]
REVIEW.
PubMed=22906767; DOI=10.1016/j.cytogfr.2012.07.003;
Sgorbissa A., Brancolini C.;
"IFNs, ISGylation and cancer: Cui prodest?";
Cytokine Growth Factor Rev. 23:307-314(2012).
[42]
FUNCTION IN UBE2N AND UBA7 ISGYLATION, AND DISULFIDE BOND.
PubMed=22693631; DOI=10.1371/journal.pone.0038294;
Bade V.N., Nickels J., Keusekotten K., Praefcke G.J.;
"Covalent protein modification with ISG15 via a conserved cysteine in
the hinge region.";
PLoS ONE 7:E38294-E38294(2012).
[43]
FUNCTION, INDUCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND
INVOLVEMENT IN IMD38.
PubMed=22859821; DOI=10.1126/science.1224026;
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., 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.;
"Mycobacterial disease and impaired IFN-gamma immunity in humans with
inherited ISG15 deficiency.";
Science 337:1684-1688(2012).
[44]
REVIEW.
PubMed=22964713; DOI=10.1038/cr.2012.133;
Fan J.B., Zhang D.E.;
"ISG15 regulates IFN-? immunity in human mycobacterial disease.";
Cell Res. 23:173-175(2013).
[45]
REVIEW.
PubMed=23579383; DOI=10.1038/emm.2013.36;
Bogunovic D., Boisson-Dupuis S., Casanova J.L.;
"ISG15: leading a double life as a secreted molecule.";
Exp. Mol. Med. 45:E18-E18(2013).
[46]
FUNCTION IN EIF2AK2 ISGYLATION.
PubMed=23229543; DOI=10.1074/jbc.M112.401851;
Okumura F., Okumura A.J., Uematsu K., Hatakeyama S., Zhang D.E.,
Kamura T.;
"Activation of double-stranded RNA-activated protein kinase (PKR) by
interferon-stimulated gene 15 (ISG15) modification down-regulates
protein translation.";
J. Biol. Chem. 288:2839-2847(2013).
[47]
REVIEW.
PubMed=23414970; DOI=10.1016/j.tim.2013.01.005;
Zhao C., Collins M.N., Hsiang T.Y., Krug R.M.;
"Interferon-induced ISG15 pathway: an ongoing virus-host battle.";
Trends Microbiol. 21:181-186(2013).
[48]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[49]
INTERACTION WITH VACCINIA VIRUS PROTEIN E3.
PubMed=24257616; DOI=10.1128/JVI.03293-13;
Eduardo-Correia B., Martinez-Romero C., Garcia-Sastre A., Guerra S.;
"ISG15 is counteracted by vaccinia virus E3 protein and controls the
proinflammatory response against viral infection.";
J. Virol. 88:2312-2318(2014).
[50]
X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-155 OF MUTANT SER-78.
PubMed=15917233; DOI=10.1074/jbc.M502814200;
Narasimhan J., Wang M., Fu Z., Klein J.M., Haas A.L., Kim J.J.;
"Crystal structure of the interferon-induced ubiquitin-like protein
ISG15.";
J. Biol. Chem. 280:27356-27365(2005).
[51]
STRUCTURE BY NMR OF 79-157.
Northeast structural genomics consortium (NESG);
"Solution NMR structure of the C-terminal domain of the interferon
alpha-inducible ISG15 protein from Homo sapiens.";
Submitted (FEB-2009) to the PDB data bank.
-!- 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 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. {ECO:0000269|PubMed:1373138,
ECO:0000269|PubMed:16009940, ECO:0000269|PubMed:16112642,
ECO:0000269|PubMed:16428300, ECO:0000269|PubMed:16434471,
ECO:0000269|PubMed:16872604, ECO:0000269|PubMed:18305167,
ECO:0000269|PubMed:19270716, ECO:0000269|PubMed:19357168,
ECO:0000269|PubMed:2005397, ECO:0000269|PubMed:20133869,
ECO:0000269|PubMed:20308324, ECO:0000269|PubMed:20639253,
ECO:0000269|PubMed:21543490, ECO:0000269|PubMed:22693631,
ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:23229543,
ECO:0000269|PubMed:7526157, ECO:0000269|PubMed:8550581}.
-!- SUBUNIT: Homodimer; disulfide-linked. Interacts with, and is
conjugated to its targets by the UBE1L (E1 enzyme) and UBE2E2 (E2
enzyme) (Probable). Interacts with NEDD4.
{ECO:0000269|PubMed:15131269, ECO:0000269|PubMed:18305167,
ECO:0000269|PubMed:22693631, ECO:0000305}.
-!- SUBUNIT: (Microbial infection) Interacts with vaccinia virus
protein E3. {ECO:0000269|PubMed:24257616}.
-!- SUBUNIT: (Microbial infection) Interaction with influenza B NS1
protein inhibits its conjugation. {ECO:0000269|PubMed:11157743}.
-!- INTERACTION:
O75369:FLNB; NbExp=4; IntAct=EBI-746466, EBI-352089;
Q6TQR6:L (xeno); NbExp=5; IntAct=EBI-746466, EBI-4403908;
P03495:NS (xeno); NbExp=4; IntAct=EBI-746466, EBI-2548993;
P03502:NS (xeno); NbExp=4; IntAct=EBI-746466, EBI-15938710;
O75688:PPM1B; NbExp=2; IntAct=EBI-746466, EBI-1047039;
P41226:UBA7; NbExp=11; IntAct=EBI-746466, EBI-751921;
Q9UMW8:USP18; NbExp=9; IntAct=EBI-746466, EBI-356206;
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22859821}.
Secreted {ECO:0000269|PubMed:22859821}. Note=Exists in three
distinct states: free within the cell, released into the
extracellular space, or conjugated to target proteins.
-!- TISSUE SPECIFICITY: 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.
{ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:7490683}.
-!- INDUCTION: Strongly induced upon exposure to type I interferons,
viruses, LPS, and other stresses, including certain genotoxic
stresses. {ECO:0000269|PubMed:22859821}.
-!- 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
(PubMed:18356159). {ECO:0000269|PubMed:18356159}.
-!- PTM: S-nitrosylation decreases its dimerization, thereby
increasing the availability as well as the solubility of monomeric
ISG15 for its conjugation to cellular proteins.
{ECO:0000269|PubMed:18606809}.
-!- PTM: 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. {ECO:0000269|PubMed:2477469,
ECO:0000269|PubMed:3350799}.
-!- DISEASE: Immunodeficiency 38, with basal ganglia calcification
(IMD38) [MIM:616126]: A 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.
{ECO:0000269|PubMed:22859821}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-----------------------------------------------------------------------
Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
Distributed under the Creative Commons Attribution-NoDerivs License
-----------------------------------------------------------------------
EMBL; M13755; AAA36038.1; -; mRNA.
EMBL; M21786; AAA36128.1; -; Genomic_DNA.
EMBL; AY168648; AAN86983.1; -; mRNA.
EMBL; BT007297; AAP35961.1; -; mRNA.
EMBL; AL645608; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CH471183; EAW56295.1; -; Genomic_DNA.
EMBL; BC009507; AAH09507.1; -; mRNA.
CCDS; CCDS6.1; -.
PIR; A28304; A28138.
RefSeq; NP_005092.1; NM_005101.3.
UniGene; Hs.458485; -.
PDB; 1Z2M; X-ray; 2.50 A; A=1-155.
PDB; 2HJ8; NMR; -; A=79-157.
PDB; 3PHX; X-ray; 1.60 A; B=79-156.
PDB; 3PSE; X-ray; 2.30 A; B=1-156.
PDB; 3R66; X-ray; 2.30 A; C/D=1-157.
PDB; 3RT3; X-ray; 2.01 A; B=1-158.
PDB; 3SDL; X-ray; 2.29 A; C/D=1-157.
PDB; 5TL6; X-ray; 2.62 A; A/C=80-157.
PDB; 5W8T; X-ray; 2.76 A; B/D=80-156.
PDB; 5W8U; X-ray; 2.41 A; B/D=80-156.
PDB; 6FFA; X-ray; 1.50 A; B=79-155.
PDBsum; 1Z2M; -.
PDBsum; 2HJ8; -.
PDBsum; 3PHX; -.
PDBsum; 3PSE; -.
PDBsum; 3R66; -.
PDBsum; 3RT3; -.
PDBsum; 3SDL; -.
PDBsum; 5TL6; -.
PDBsum; 5W8T; -.
PDBsum; 5W8U; -.
PDBsum; 6FFA; -.
ProteinModelPortal; P05161; -.
SMR; P05161; -.
BioGrid; 114995; 195.
DIP; DIP-29814N; -.
IntAct; P05161; 42.
MINT; P05161; -.
STRING; 9606.ENSP00000368699; -.
iPTMnet; P05161; -.
PhosphoSitePlus; P05161; -.
BioMuta; ISG15; -.
DMDM; 52001470; -.
EPD; P05161; -.
MaxQB; P05161; -.
PaxDb; P05161; -.
PeptideAtlas; P05161; -.
PRIDE; P05161; -.
TopDownProteomics; P05161; -.
DNASU; 9636; -.
Ensembl; ENST00000379389; ENSP00000368699; ENSG00000187608.
GeneID; 9636; -.
KEGG; hsa:9636; -.
UCSC; uc001acj.5; human.
CTD; 9636; -.
DisGeNET; 9636; -.
EuPathDB; HostDB:ENSG00000187608.8; -.
GeneCards; ISG15; -.
HGNC; HGNC:4053; ISG15.
HPA; HPA004627; -.
MalaCards; ISG15; -.
MIM; 147571; gene.
MIM; 616126; phenotype.
neXtProt; NX_P05161; -.
OpenTargets; ENSG00000187608; -.
Orphanet; 319563; Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency.
PharmGKB; PA28465; -.
eggNOG; KOG0001; Eukaryota.
eggNOG; COG5272; LUCA.
GeneTree; ENSGT00810000125435; -.
HOGENOM; HOG000233942; -.
HOVERGEN; HBG000057; -.
InParanoid; P05161; -.
KO; K12159; -.
OMA; FWLTFEG; -.
OrthoDB; EOG091G178I; -.
PhylomeDB; P05161; -.
TreeFam; TF338379; -.
Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
Reactome; R-HSA-168276; NS1 Mediated Effects on Host Pathways.
Reactome; R-HSA-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta.
Reactome; R-HSA-5656169; Termination of translesion DNA synthesis.
Reactome; R-HSA-909733; Interferon alpha/beta signaling.
Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
ChiTaRS; ISG15; human.
EvolutionaryTrace; P05161; -.
GeneWiki; ISG15; -.
GenomeRNAi; 9636; -.
PRO; PR:P05161; -.
Proteomes; UP000005640; Chromosome 1.
Bgee; ENSG00000187608; -.
CleanEx; HS_ISG15; -.
ExpressionAtlas; P05161; baseline and differential.
Genevisible; P05161; HS.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
GO; GO:0031386; F:protein tag; IEA:Ensembl.
GO; GO:0042742; P:defense response to bacterium; IMP:UniProtKB.
GO; GO:0051607; P:defense response to virus; IMP:UniProtKB.
GO; GO:0032020; P:ISG15-protein conjugation; IDA:UniProtKB.
GO; GO:0019941; P:modification-dependent protein catabolic process; IEA:Ensembl.
GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB.
GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
GO; GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB.
GO; GO:0030501; P:positive regulation of bone mineralization; ISS:UniProtKB.
GO; GO:0045648; P:positive regulation of erythrocyte differentiation; IEA:Ensembl.
GO; GO:0032649; P:regulation of interferon-gamma production; IMP:UniProtKB.
GO; GO:0034340; P:response to type I interferon; IDA:UniProtKB.
GO; GO:0019985; P:translesion synthesis; TAS:Reactome.
GO; GO:0060337; P:type I interferon signaling pathway; TAS:Reactome.
GO; GO:0016032; P:viral process; IEA:UniProtKB-KW.
InterPro; IPR019956; Ubiquitin.
InterPro; IPR029071; Ubiquitin-like_domsf.
InterPro; IPR000626; Ubiquitin_dom.
Pfam; PF00240; ubiquitin; 2.
PRINTS; PR00348; UBIQUITIN.
SMART; SM00213; UBQ; 2.
SUPFAM; SSF54236; SSF54236; 2.
PROSITE; PS50053; UBIQUITIN_2; 2.
1: Evidence at protein level;
3D-structure; Antiviral defense; Complete proteome; Cytoplasm;
Direct protein sequencing; Disulfide bond; Host-virus interaction;
Immunity; Innate immunity; Isopeptide bond; Polymorphism;
Reference proteome; Repeat; S-nitrosylation; Secreted;
Ubl conjugation pathway.
INIT_MET 1 1 Removed. {ECO:0000269|PubMed:2477469}.
CHAIN 2 157 Ubiquitin-like protein ISG15.
/FTId=PRO_0000035986.
PROPEP 158 165 Removed in mature form.
/FTId=PRO_0000035987.
DOMAIN 2 78 Ubiquitin-like 1. {ECO:0000255|PROSITE-
ProRule:PRU00214}.
DOMAIN 79 157 Ubiquitin-like 2. {ECO:0000255|PROSITE-
ProRule:PRU00214}.
REGION 153 157 Involved in the ligation of specific
target proteins. {ECO:0000250}.
MOTIF 152 157 LRLRGG.
BINDING 153 153 Activating enzyme. {ECO:0000250}.
MOD_RES 78 78 S-nitrosocysteine; alternate.
{ECO:0000269|PubMed:18606809}.
DISULFID 78 78 Interchain (with C-87 in UBE2N);
alternate. {ECO:0000269|PubMed:22693631}.
CROSSLNK 157 157 Glycyl lysine isopeptide (Gly-Lys)
(interchain with K-? in acceptor
proteins). {ECO:0000255|PROSITE-
ProRule:PRU00214}.
VARIANT 83 83 S -> N (in dbSNP:rs1921).
{ECO:0000269|PubMed:15489334,
ECO:0000269|Ref.5, ECO:0000269|Ref.6}.
/FTId=VAR_016181.
CONFLICT 35 35 K -> N (in Ref. 2; AAA36128).
{ECO:0000305}.
STRAND 4 9 {ECO:0000244|PDB:3RT3}.
STRAND 14 18 {ECO:0000244|PDB:3RT3}.
HELIX 25 36 {ECO:0000244|PDB:3RT3}.
HELIX 40 42 {ECO:0000244|PDB:3RT3}.
STRAND 43 48 {ECO:0000244|PDB:3RT3}.
STRAND 56 58 {ECO:0000244|PDB:3SDL}.
HELIX 60 63 {ECO:0000244|PDB:3RT3}.
STRAND 70 75 {ECO:0000244|PDB:3RT3}.
STRAND 82 87 {ECO:0000244|PDB:3PHX}.
STRAND 93 98 {ECO:0000244|PDB:3PHX}.
HELIX 104 115 {ECO:0000244|PDB:3PHX}.
HELIX 119 121 {ECO:0000244|PDB:3PHX}.
STRAND 122 126 {ECO:0000244|PDB:3PHX}.
STRAND 129 131 {ECO:0000244|PDB:5TL6}.
HELIX 137 140 {ECO:0000244|PDB:3PHX}.
STRAND 147 152 {ECO:0000244|PDB:3PHX}.
SEQUENCE 165 AA; 17888 MW; B6858A15AB0FFFDE CRC64;
MGWDLTVKML AGNEFQVSLS SSMSVSELKA QITQKIGVHA FQQRLAVHPS GVALQDRVPL
ASQGLGPGST VLLVVDKCDE PLSILVRNNK GRSSTYEVRL TQTVAHLKQQ VSGLEGVQDD
LFWLTFEGKP LEDQLPLGEY GLKPLSTVFM NLRLRGGGTE PGGRS


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