ID ISG15_HUMAN Reviewed; 165 AA. AC P05161; Q5SVA4; Q7Z2G2; Q96GF0; DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 5. DT 27-MAR-2024, entry version 238. DE RecName: Full=Ubiquitin-like protein ISG15; DE AltName: Full=Interferon-induced 15 kDa protein; DE AltName: Full=Interferon-induced 17 kDa protein; DE Short=IP17; DE AltName: Full=Ubiquitin cross-reactive protein; DE Short=hUCRP; DE Flags: Precursor; GN Name=ISG15 {ECO:0000312|HGNC:HGNC:4053}; Synonyms=G1P2, UCRP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3087979; DOI=10.1016/s0021-9258(19)84453-8; RA Blomstrom D.C., Fahey D., Kutny R., Korant B.D., Knight E. Jr.; RT "Molecular characterization of the interferon-induced 15-kDa protein. RT Molecular cloning and nucleotide and amino acid sequence."; RL J. Biol. Chem. 261:8811-8816(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3476954; DOI=10.1073/pnas.84.18.6394; RA Reich N., Evans B., Levy D., Fahey D., Knight E. Jr., Darnell J.E. Jr.; RT "Interferon-induced transcription of a gene encoding a 15-kDa protein RT depends on an upstream enhancer element."; RL Proc. Natl. Acad. Sci. U.S.A. 84:6394-6398(1987). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEOLYTIC PROCESSING. RX PubMed=3350799; DOI=10.1016/s0021-9258(18)68812-x; RA Knight E. Jr., Fahey D., Cordova B., Hillman M. Jr., Kutny R., Reich N., RA Blomstrom D.C.; RT "A 15-kDa interferon-induced protein is derived by COOH-terminal processing RT of a 17-kDa precursor."; RL J. Biol. Chem. 263:4520-4522(1988). RN [4] RP ERRATUM OF PUBMED:3350799. RA Knight E. Jr., Fahey D., Cordova B., Hillman M. Jr., Kutny R., Reich N., RA Blomstrom D.C.; RL J. Biol. Chem. 263:10040-10040(1988). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASN-83. RC TISSUE=Testis; RA Kamitani T., Fukuda-Kamitani T.; RT "Conjugation by ubiquitin-like proteins."; RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-83. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-83. RC TISSUE=Colon; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP PROTEIN SEQUENCE OF 2-38 AND 151-165, AND PROTEOLYTIC PROCESSING. RX PubMed=2477469; DOI=10.1089/jir.1989.9.493; RA Feltham N., Hillman M. Jr., Cordova B., Fahey D., Larsen B., RA Blomstrom D.C., Knight E. Jr.; RT "A 15-kD interferon-induced protein and its 17-kD precursor: expression in RT Escherichia coli, purification, and characterization."; RL J. Interferon Res. 9:493-507(1989). RN [11] RP SIMILARITY TO UBIQUITIN. RX PubMed=2440890; DOI=10.1016/s0021-9258(18)60961-5; RA Haas A.L., Ahrens P., Bright P.M., Ankel H.; RT "Interferon induces a 15-kilodalton protein exhibiting marked homology to RT ubiquitin."; RL J. Biol. Chem. 262:11315-11323(1987). RN [12] RP FUNCTION. RX PubMed=1373138; DOI=10.1016/s0021-9258(18)42585-9; RA Loeb K.R., Haas A.L.; RT "The interferon-inducible 15-kDa ubiquitin homolog conjugates to RT intracellular proteins."; RL J. Biol. Chem. 267:7806-7813(1992). RN [13] RP FUNCTION. RX PubMed=7526157; DOI=10.1128/mcb.14.12.8408-8419.1994; RA Loeb K.R., Haas A.L.; RT "Conjugates of ubiquitin cross-reactive protein distribute in a RT cytoskeletal pattern."; RL Mol. Cell. Biol. 14:8408-8419(1994). RN [14] RP FUNCTION. RX PubMed=8550581; DOI=10.1074/jbc.271.1.324; RA Narasimhan J., Potter J.L., Haas A.L.; RT "Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct RT from that of ubiquitin."; RL J. Biol. Chem. 271:324-330(1996). RN [15] RP FUNCTION. RX PubMed=2005397; RA Knight E. Jr., Cordova B.; RT "IFN-induced 15-kDa protein is released from human lymphocytes and RT monocytes."; RL J. Immunol. 146:2280-2284(1991). RN [16] RP TISSUE SPECIFICITY. RX PubMed=7490683; DOI=10.1002/path.1711770210; RA Lowe J., McDermott H., Loeb K., Landon M., Haas A.L., Mayer R.J.; RT "Immunohistochemical localization of ubiquitin cross-reactive protein in RT human tissues."; RL J. Pathol. 177:163-169(1995). RN [17] RP INTERACTION WITH UBE1L AND INFLUENZA B NS1. RX PubMed=11157743; DOI=10.1093/emboj/20.3.362; RA Yuan W., Krug R.M.; RT "Influenza B virus NS1 protein inhibits conjugation of the interferon RT (IFN)-induced ubiquitin-like ISG15 protein."; RL EMBO J. 20:362-371(2001). RN [18] RP CHARACTERIZATION. RX PubMed=11788588; DOI=10.1074/jbc.m109078200; RA Malakhov M.P., Malakhova O.A., Kim K.I., Ritchie K.J., Zhang D.-E.; RT "UBP43 (USP18) specifically removes ISG15 from conjugated proteins."; RL J. Biol. Chem. 277:9976-9981(2002). RN [19] RP INTERACTION WITH UBE2E2. RX PubMed=15131269; DOI=10.1073/pnas.0402528101; RA Zhao C., Beaudenon S.L., Kelley M.L., Waddell M.B., Yuan W., Schulman B.A., RA Huibregtse J.M., Krug R.M.; RT "The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN- RT alpha/beta-induced ubiquitin-like protein."; RL Proc. Natl. Acad. Sci. U.S.A. 101:7578-7582(2004). RN [20] RP FUNCTION IN UBE2N ISGYLATION. RX PubMed=16112642; DOI=10.1016/j.bbrc.2005.08.034; RA Takeuchi T., Yokosawa H.; RT "ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating RT activity."; RL Biochem. Biophys. Res. Commun. 336:9-13(2005). RN [21] RP FUNCTION IN UBE2E1 AND UBE2L6 ISGYLATION. RX PubMed=16428300; DOI=10.1093/jb/mvi172; RA Takeuchi T., Iwahara S., Saeki Y., Sasajima H., Yokosawa H.; RT "Link between the ubiquitin conjugation system and the ISG15 conjugation RT system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme."; RL J. Biochem. 138:711-719(2005). RN [22] RP FUNCTION IN IFIT1; RIGI AND MX1 ISGYLATION. RX PubMed=16009940; DOI=10.1073/pnas.0504754102; RA Zhao C., Denison C., Huibregtse J.M., Gygi S.P., Krug R.M.; RT "Human ISG15 conjugation targets both IFN-induced and constitutively RT expressed proteins functioning in diverse cellular pathways."; RL Proc. Natl. Acad. Sci. U.S.A. 102:10200-10205(2005). RN [23] RP FUNCTION IN PPM1B ISGYLATION. RX PubMed=16872604; DOI=10.1016/j.febslet.2006.07.032; RA Takeuchi T., Kobayashi T., Tamura S., Yokosawa H.; RT "Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation."; RL FEBS Lett. 580:4521-4526(2006). RN [24] RP FUNCTION IN HIV-1 RESTRICTION. RX PubMed=16434471; DOI=10.1073/pnas.0510518103; RA Okumura A., Lu G., Pitha-Rowe I., Pitha P.M.; RT "Innate antiviral response targets HIV-1 release by the induction of RT ubiquitin-like protein ISG15."; RL Proc. Natl. Acad. Sci. U.S.A. 103:1440-1445(2006). RN [25] RP DOMAINS UBIQUITIN-LIKE 1 AND 2. RX PubMed=18356159; DOI=10.1074/jbc.m800162200; RA Chang Y.G., Yan X.Z., Xie Y.Y., Gao X.C., Song A.X., Zhang D.E., Hu H.Y.; RT "Different roles for two ubiquitin-like domains of ISG15 in protein RT modification."; RL J. Biol. Chem. 283:13370-13377(2008). RN [26] RP S-NITROSYLATION AT CYS-78. RX PubMed=18606809; DOI=10.1074/jbc.m803795200; RA Okumura F., Lenschow D.J., Zhang D.E.; RT "Nitrosylation of ISG15 prevents the disulfide bond-mediated dimerization RT of ISG15 and contributes to effective ISGylation."; RL J. Biol. Chem. 283:24484-24488(2008). RN [27] RP FUNCTION IN EBOLA VIRUS RESTRICTION, AND INTERACTION WITH NEDD4. RX PubMed=18305167; DOI=10.1073/pnas.0710629105; RA Okumura A., Pitha P.M., Harty R.N.; RT "ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by RT blocking Nedd4 ligase activity."; RL Proc. Natl. Acad. Sci. U.S.A. 105:3974-3979(2008). RN [28] RP FUNCTION IN FLNB ISGYLATION. RX PubMed=19270716; DOI=10.1038/embor.2009.23; RA Jeon Y.J., Choi J.S., Lee J.Y., Yu K.R., Kim S.M., Ka S.H., Oh K.H., RA Kim K.I., Zhang D.E., Bang O.S., Chung C.H.; RT "ISG15 modification of filamin B negatively regulates the type I RT interferon-induced JNK signalling pathway."; RL EMBO Rep. 10:374-380(2009). RN [29] RP REVIEW. RX PubMed=19680460; DOI=10.1159/000226245; RA Harty R.N., Pitha P.M., Okumura A.; RT "Antiviral activity of innate immune protein ISG15."; RL J. Innate Immun. 1:397-404(2009). RN [30] RP FUNCTION IN INFLUENZA A VIRUS RESTRICTION. RX PubMed=19357168; DOI=10.1128/jvi.01667-08; RA Hsiang T.Y., Zhao C., Krug R.M.; RT "Interferon-induced ISG15 conjugation inhibits influenza A virus gene RT expression and replication in human cells."; RL J. Virol. 83:5971-5977(2009). RN [31] RP REVIEW. RX PubMed=20153823; DOI=10.1016/j.bbadis.2010.02.006; RA Jeon Y.J., Yoo H.M., Chung C.H.; RT "ISG15 and immune diseases."; RL Biochim. Biophys. Acta 1802:485-496(2010). RN [32] RP REVIEW. RX PubMed=20946978; DOI=10.1016/j.cell.2010.09.033; RA Skaug B., Chen Z.J.; RT "Emerging role of ISG15 in antiviral immunity."; RL Cell 143:187-190(2010). RN [33] RP FUNCTION. RX PubMed=20639253; DOI=10.1136/gut.2009.195545; RA Broering R., Zhang X., Kottilil S., Trippler M., Jiang M., Lu M., RA Gerken G., Schlaak J.F.; RT "The interferon stimulated gene 15 functions as a proviral factor for the RT hepatitis C virus and as a regulator of the IFN response."; RL Gut 59:1111-1119(2010). RN [34] RP FUNCTION IN IRF3 ISGYLATION. RX PubMed=20308324; DOI=10.1128/mcb.01466-09; RA Shi H.X., Yang K., Liu X., Liu X.Y., Wei B., Shan Y.F., Zhu L.H., Wang C.; RT "Positive regulation of interferon regulatory factor 3 activation by Herc5 RT via ISG15 modification."; RL Mol. Cell. Biol. 30:2424-2436(2010). RN [35] RP FUNCTION IN INFLUENZA A VIRUS NS1 ISGYLATION. RX PubMed=20133869; DOI=10.1073/pnas.0909144107; RA Zhao C., Hsiang T.Y., Kuo R.L., Krug R.M.; RT "ISG15 conjugation system targets the viral NS1 protein in influenza A RT virus-infected cells."; RL Proc. Natl. Acad. Sci. U.S.A. 107:2253-2258(2010). RN [36] RP REVIEW. RX PubMed=21994614; DOI=10.3390/v2102154; RA Lenschow D.J.; RT "Antiviral properties of ISG15."; RL Viruses 2:2154-2168(2010). RN [37] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [38] RP REVIEW. RX PubMed=21190487; DOI=10.1089/jir.2010.0110; RA Zhang D., Zhang D.E.; RT "Interferon-stimulated gene 15 and the protein ISGylation system."; RL J. Interferon Cytokine Res. 31:119-130(2011). RN [39] RP FUNCTION IN CHMP5; CHMP2A; CHMP4B AND CHMP6 ISGYLATION. RX PubMed=21543490; DOI=10.1128/jvi.02610-10; RA Kuang Z., Seo E.J., Leis J.; RT "Mechanism of inhibition of retrovirus release from cells by interferon- RT induced gene ISG15."; RL J. Virol. 85:7153-7161(2011). RN [40] RP INTERACTION WITH CRIMEAN-CONGO HEMORRHAGIC FEVER VIRUS RNA-DIRECTED RNA RP POLYMERASE L (MICROBIAL INFECTION). RX PubMed=21266548; DOI=10.1073/pnas.1015287108; RA Akutsu M., Ye Y., Virdee S., Chin J.W., Komander D.; RT "Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian RT tumor domains."; RL Proc. Natl. Acad. Sci. U.S.A. 108:2228-2233(2011). RN [41] RP INTERACTION WITH CRIMEAN-CONGO HEMORRHAGIC FEVER VIRUS RNA-DIRECTED RNA RP POLYMERASE L (MICROBIAL INFECTION). RX PubMed=21245344; DOI=10.1073/pnas.1013388108; RA James T.W., Frias-Staheli N., Bacik J.P., Levingston Macleod J.M., RA Khajehpour M., Garcia-Sastre A., Mark B.L.; RT "Structural basis for the removal of ubiquitin and interferon-stimulated RT gene 15 by a viral ovarian tumor domain-containing protease."; RL Proc. Natl. Acad. Sci. U.S.A. 108:2222-2227(2011). RN [42] RP REVIEW. RX PubMed=22666250; DOI=10.1155/2012/532723; RA Seo E.J., Leis J.; RT "Budding of enveloped viruses: interferon-induced ISG15-antivirus RT mechanisms targeting the release process."; RL Adv. Virol. 2012:532723-532723(2012). RN [43] RP REVIEW. RX PubMed=22906767; DOI=10.1016/j.cytogfr.2012.07.003; RA Sgorbissa A., Brancolini C.; RT "IFNs, ISGylation and cancer: Cui prodest?"; RL Cytokine Growth Factor Rev. 23:307-314(2012). RN [44] RP FUNCTION IN UBE2N AND UBA7 ISGYLATION, AND DISULFIDE BOND. RX PubMed=22693631; DOI=10.1371/journal.pone.0038294; RA Bade V.N., Nickels J., Keusekotten K., Praefcke G.J.; RT "Covalent protein modification with ISG15 via a conserved cysteine in the RT hinge region."; RL PLoS ONE 7:E38294-E38294(2012). RN [45] RP FUNCTION, INDUCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND RP INVOLVEMENT IN IMD38. RX PubMed=22859821; DOI=10.1126/science.1224026; RA Bogunovic D., Byun M., Durfee L.A., Abhyankar A., Sanal O., Mansouri D., RA Salem S., Radovanovic I., Grant A.V., Adimi P., Mansouri N., Okada S., RA Bryant V.L., Kong X.F., Kreins A., Velez M.M., Boisson B., Khalilzadeh S., RA Ozcelik U., Darazam I.A., Schoggins J.W., Rice C.M., Al-Muhsen S., Behr M., RA Vogt G., Puel A., Bustamante J., Gros P., Huibregtse J.M., Abel L., RA Boisson-Dupuis S., Casanova J.L.; RT "Mycobacterial disease and impaired IFN-gamma immunity in humans with RT inherited ISG15 deficiency."; RL Science 337:1684-1688(2012). RN [46] RP REVIEW. RX PubMed=22964713; DOI=10.1038/cr.2012.133; RA Fan J.B., Zhang D.E.; RT "ISG15 regulates IFN-? immunity in human mycobacterial disease."; RL Cell Res. 23:173-175(2013). RN [47] RP REVIEW. RX PubMed=23579383; DOI=10.1038/emm.2013.36; RA Bogunovic D., Boisson-Dupuis S., Casanova J.L.; RT "ISG15: leading a double life as a secreted molecule."; RL Exp. Mol. Med. 45:E18-E18(2013). RN [48] RP FUNCTION IN EIF2AK2 ISGYLATION. RX PubMed=23229543; DOI=10.1074/jbc.m112.401851; RA Okumura F., Okumura A.J., Uematsu K., Hatakeyama S., Zhang D.E., Kamura T.; RT "Activation of double-stranded RNA-activated protein kinase (PKR) by RT interferon-stimulated gene 15 (ISG15) modification down-regulates protein RT translation."; RL J. Biol. Chem. 288:2839-2847(2013). RN [49] RP REVIEW. RX PubMed=23414970; DOI=10.1016/j.tim.2013.01.005; RA Zhao C., Collins M.N., Hsiang T.Y., Krug R.M.; RT "Interferon-induced ISG15 pathway: an ongoing virus-host battle."; RL Trends Microbiol. 21:181-186(2013). RN [50] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [51] RP INTERACTION WITH VACCINIA VIRUS PROTEIN E3. RX PubMed=24257616; DOI=10.1128/jvi.03293-13; RA Eduardo-Correia B., Martinez-Romero C., Garcia-Sastre A., Guerra S.; RT "ISG15 is counteracted by vaccinia virus E3 protein and controls the RT proinflammatory response against viral infection."; RL J. Virol. 88:2312-2318(2014). RN [52] RP FUNCTION, AND INTERACTION WITH HUMAN CYTOMEGALOVIRUS PROTEIN UL26 RP (MICROBIAL INFECTION). RX PubMed=27564865; DOI=10.1371/journal.ppat.1005850; RA Kim Y.J., Kim E.T., Kim Y.E., Lee M.K., Kwon K.M., Kim K.I., Stamminger T., RA Ahn J.H.; RT "Consecutive Inhibition of ISG15 Expression and ISGylation by RT Cytomegalovirus Regulators."; RL PLoS Pathog. 12:e1005850-e1005850(2016). RN [53] RP FUNCTION, AND MUTAGENESIS OF ARG-44; SER-83; TYR-96; ARG-99; THR-101; RP GLN-102 AND THR-103. RX PubMed=29100055; DOI=10.1016/j.molcel.2017.10.003; RA Swaim C.D., Scott A.F., Canadeo L.A., Huibregtse J.M.; RT "Extracellular ISG15 signals cytokine secretion through the LFA-1 integrin RT receptor."; RL Mol. Cell 68:581-590(2017). RN [54] RP FUNCTION. RX PubMed=33727702; DOI=10.1038/s41564-021-00884-1; RA Liu G., Lee J.H., Parker Z.M., Acharya D., Chiang J.J., van Gent M., RA Riedl W., Davis-Gardner M.E., Wies E., Chiang C., Gack M.U.; RT "ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS- RT CoV-2 papain-like protease to evade host innate immunity."; RL Nat. Microbiol. 6:467-478(2021). RN [55] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-155 OF MUTANT SER-78. RX PubMed=15917233; DOI=10.1074/jbc.m502814200; RA Narasimhan J., Wang M., Fu Z., Klein J.M., Haas A.L., Kim J.J.; RT "Crystal structure of the interferon-induced ubiquitin-like protein RT ISG15."; RL J. Biol. Chem. 280:27356-27365(2005). RN [56] RP STRUCTURE BY NMR OF 79-157. RG Northeast structural genomics consortium (NESG); RT "Solution NMR structure of the C-terminal domain of the interferon alpha- RT inducible ISG15 protein from Homo sapiens."; RL Submitted (FEB-2009) to the PDB data bank. CC -!- FUNCTION: Ubiquitin-like protein which plays a key role in the innate CC immune response to viral infection either via its conjugation to a CC target protein (ISGylation) or via its action as a free or unconjugated CC protein (PubMed:27564865). ISGylation involves a cascade of enzymatic CC reactions involving E1, E2, and E3 enzymes which catalyze the CC conjugation of ISG15 to a lysine residue in the target protein CC (PubMed:33727702). Its target proteins include IFIT1, MX1/MxA, PPM1B, CC UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral CC sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers CC activation of innate immunity against a range of viruses, including CC coronaviruses, flaviviruses and picornaviruses (PubMed:33727702). Can CC also isgylate: EIF2AK2/PKR which results in its activation, RIGI which CC inhibits its function in antiviral signaling response, EIF4E2 which CC enhances its cap structure-binding activity and translation-inhibition CC activity, UBE2N and UBE2E1 which negatively regulates their activity, CC IRF3 which inhibits its ubiquitination and degradation and FLNB which CC prevents its ability to interact with the upstream activators of the CC JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits CC antiviral activity towards both DNA and RNA viruses, including CC influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via CC disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag CC and host TSG101 and disrupts their interaction, thereby preventing CC assembly and release of virions from infected cells. Inhibits Ebola CC virus budding mediated by the VP40 protein by disrupting ubiquitin CC ligase activity of NEDD4 and its ability to ubiquitinate VP40. CC ISGylates influenza A virus NS1 protein which causes a loss of function CC of the protein and the inhibition of virus replication. The secreted CC form of ISG15 can: induce natural killer cell proliferation, act as a CC chemotactic factor for neutrophils and act as a IFN-gamma-inducing CC cytokine playing an essential role in antimycobacterial immunity. The CC secreted form acts through the integrin ITGAL/ITGB2 receptor to CC initiate activation of SRC family tyrosine kinases including LYN, HCK CC and FGR which leads to secretion of IFNG and IL10; the interaction is CC mediated by ITGAL (PubMed:29100055). {ECO:0000269|PubMed:1373138, CC ECO:0000269|PubMed:16009940, ECO:0000269|PubMed:16112642, CC ECO:0000269|PubMed:16428300, ECO:0000269|PubMed:16434471, CC ECO:0000269|PubMed:16872604, ECO:0000269|PubMed:18305167, CC ECO:0000269|PubMed:19270716, ECO:0000269|PubMed:19357168, CC ECO:0000269|PubMed:2005397, ECO:0000269|PubMed:20133869, CC ECO:0000269|PubMed:20308324, ECO:0000269|PubMed:20639253, CC ECO:0000269|PubMed:21543490, ECO:0000269|PubMed:22693631, CC ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:23229543, CC ECO:0000269|PubMed:27564865, ECO:0000269|PubMed:29100055, CC ECO:0000269|PubMed:33727702, ECO:0000269|PubMed:7526157, CC ECO:0000269|PubMed:8550581}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:2440890). Interacts with, CC and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 CC enzyme) (PubMed:11157743, PubMed:15131269). Interacts with NEDD4 CC (PubMed:18305167). {ECO:0000269|PubMed:11157743, CC ECO:0000269|PubMed:15131269, ECO:0000269|PubMed:18305167, CC ECO:0000269|PubMed:2440890}. CC -!- SUBUNIT: (Microbial infection) Interacts with vaccinia virus protein CC E3. {ECO:0000269|PubMed:24257616}. CC -!- SUBUNIT: (Microbial infection) Interaction with influenza B NS1 protein CC inhibits its conjugation. {ECO:0000269|PubMed:11157743}. CC -!- SUBUNIT: (Microbial infection) Interacts (via C-terminus) with Crimean- CC Congo hemorrhagic fever virus (CCHFV) RNA-directed RNA polymerase L CC (via N-terminus); the deISGylase activity of the viral protein CC interferes with antiviral signaling pathways mediated by NF-kappaB and CC IRF signalings. {ECO:0000269|PubMed:21266548}. CC -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus CC protein UL26; this interaction inhibits global protein ISGylation. CC {ECO:0000269|PubMed:27564865}. CC -!- INTERACTION: CC P05161; O75369: FLNB; NbExp=4; IntAct=EBI-746466, EBI-352089; CC P05161; Q9BYX4: IFIH1; NbExp=7; IntAct=EBI-746466, EBI-6115771; CC P05161; Q14653: IRF3; NbExp=2; IntAct=EBI-746466, EBI-2650369; CC P05161; O75688: PPM1B; NbExp=2; IntAct=EBI-746466, EBI-1047039; CC P05161; O60260-5: PRKN; NbExp=3; IntAct=EBI-746466, EBI-21251460; CC P05161; P41226: UBA7; NbExp=10; IntAct=EBI-746466, EBI-751921; CC P05161; Q9UMW8: USP18; NbExp=9; IntAct=EBI-746466, EBI-356206; CC P05161; PRO_0000338257 [P0C6U8]: 1a; Xeno; NbExp=5; IntAct=EBI-746466, EBI-25635190; CC P05161; Q6TQR6: L; Xeno; NbExp=5; IntAct=EBI-746466, EBI-4403908; CC P05161; P03495: NS; Xeno; NbExp=4; IntAct=EBI-746466, EBI-2548993; CC P05161; P03502: NS; Xeno; NbExp=4; IntAct=EBI-746466, EBI-15938710; CC P05161; K0BWD0: orf1ab; Xeno; NbExp=4; IntAct=EBI-746466, EBI-25565992; CC P05161; PRO_0000422441 [K9N7C7]: rep; Xeno; NbExp=4; IntAct=EBI-746466, EBI-25592237; CC P05161; PRO_0000037311 [P0C6X7]: rep; Xeno; NbExp=2; IntAct=EBI-746466, EBI-25474079; CC P05161; PRO_0000449621 [P0DTD1]: rep; Xeno; NbExp=13; IntAct=EBI-746466, EBI-25492388; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22859821}. Secreted CC {ECO:0000269|PubMed:22859821}. Note=Exists in three distinct states: CC free within the cell, released into the extracellular space, or CC conjugated to target proteins. CC -!- TISSUE SPECIFICITY: Detected in lymphoid cells, striated and smooth CC muscle, several epithelia and neurons. Expressed in neutrophils, CC monocytes and lymphocytes. Enhanced expression seen in pancreatic CC adenocarcinoma, endometrial cancer, and bladder cancer, as compared to CC non-cancerous tissue. In bladder cancer, the increase in expression CC exhibits a striking positive correlation with more advanced stages of CC the disease. {ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:7490683}. CC -!- INDUCTION: Strongly induced upon exposure to type I interferons, CC viruses, LPS, and other stresses, including certain genotoxic stresses. CC {ECO:0000269|PubMed:22859821}. CC -!- DOMAIN: Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are CC required for its efficient conjugation to cellular proteins. The two CC domains play different roles in the ISGylation pathway: Ubiquitin-like CC 2 domain is necessary for the first two steps allowing the linking of CC ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is CC essential for the final, E3-mediated transfer of ISG15, from the E2 to CC the Lys of the target protein (PubMed:18356159). CC {ECO:0000269|PubMed:18356159}. CC -!- PTM: S-nitrosylation decreases its dimerization, thereby increasing the CC availability as well as the solubility of monomeric ISG15 for its CC conjugation to cellular proteins. {ECO:0000269|PubMed:18606809}. CC -!- PTM: Induced as an inactive, precursor protein that is cleaved by CC specific proteases to expose the C-terminal diglycine (LRLRGG) motif. CC This motif is essential not only for its conjugation to substrates but CC also for its recognition by the relevant processing proteases. CC {ECO:0000269|PubMed:2477469, ECO:0000269|PubMed:3350799}. CC -!- DISEASE: Immunodeficiency 38, with basal ganglia calcification (IMD38) CC [MIM:616126]: A primary immunodeficiency predisposing individuals to CC severe clinical disease upon infection with weakly virulent CC mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin CC (BCG) vaccines. Patients are also susceptible to Salmonella and CC Mycobacterium tuberculosis infections. Affected individuals have CC intracranial calcification. {ECO:0000269|PubMed:22859821}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=On guard - Issue 240 of CC October 2021; CC URL="https://web.expasy.org/spotlight/back_issues/234/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M13755; AAA36038.1; -; mRNA. DR EMBL; M21786; AAA36128.1; -; Genomic_DNA. DR EMBL; AY168648; AAN86983.1; -; mRNA. DR EMBL; BT007297; AAP35961.1; -; mRNA. DR EMBL; AL645608; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471183; EAW56295.1; -; Genomic_DNA. DR EMBL; BC009507; AAH09507.1; -; mRNA. DR CCDS; CCDS6.1; -. DR PIR; A28304; A28138. DR RefSeq; NP_005092.1; NM_005101.3. DR PDB; 1Z2M; X-ray; 2.50 A; A=1-155. DR PDB; 2HJ8; NMR; -; A=79-157. DR PDB; 3PHX; X-ray; 1.60 A; B=79-156. DR PDB; 3PSE; X-ray; 2.30 A; B=1-156. DR PDB; 3R66; X-ray; 2.30 A; C/D=1-157. DR PDB; 3RT3; X-ray; 2.01 A; B=1-158. DR PDB; 3SDL; X-ray; 2.29 A; C/D=1-157. DR PDB; 5TL6; X-ray; 2.62 A; A/C=80-157. DR PDB; 5W8T; X-ray; 2.76 A; B/D=80-156. DR PDB; 5W8U; X-ray; 2.41 A; B/D=80-156. DR PDB; 6BI8; X-ray; 3.00 A; C/D=1-156. DR PDB; 6FFA; X-ray; 1.50 A; B=79-155. DR PDB; 6XA9; X-ray; 2.90 A; B/D/F=79-157. DR PDB; 7RBS; X-ray; 2.98 A; B/D/F/H/J=2-157. DR PDB; 7S6P; X-ray; 2.15 A; A/B/C/D/E/F=2-157. DR PDB; 8SE9; EM; 3.20 A; B/D=1-157. DR PDB; 8SEA; EM; 3.40 A; B/D=1-157. DR PDB; 8SEB; EM; 3.24 A; B=1-157. DR PDB; 8SV8; EM; 3.38 A; B/D=1-157. DR PDBsum; 1Z2M; -. DR PDBsum; 2HJ8; -. DR PDBsum; 3PHX; -. DR PDBsum; 3PSE; -. DR PDBsum; 3R66; -. DR PDBsum; 3RT3; -. DR PDBsum; 3SDL; -. DR PDBsum; 5TL6; -. DR PDBsum; 5W8T; -. DR PDBsum; 5W8U; -. DR PDBsum; 6BI8; -. DR PDBsum; 6FFA; -. DR PDBsum; 6XA9; -. DR PDBsum; 7RBS; -. DR PDBsum; 7S6P; -. DR PDBsum; 8SE9; -. DR PDBsum; 8SEA; -. DR PDBsum; 8SEB; -. DR PDBsum; 8SV8; -. DR AlphaFoldDB; P05161; -. DR BMRB; P05161; -. DR EMDB; EMD-40407; -. DR EMDB; EMD-40408; -. DR EMDB; EMD-40409; -. DR EMDB; EMD-40782; -. DR SMR; P05161; -. DR BioGRID; 114995; 490. DR DIP; DIP-29814N; -. DR IntAct; P05161; 66. DR MINT; P05161; -. DR STRING; 9606.ENSP00000496832; -. DR GlyGen; P05161; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P05161; -. DR PhosphoSitePlus; P05161; -. DR BioMuta; ISG15; -. DR DMDM; 52001470; -. DR EPD; P05161; -. DR jPOST; P05161; -. DR MassIVE; P05161; -. DR MaxQB; P05161; -. DR PaxDb; 9606-ENSP00000368699; -. DR PeptideAtlas; P05161; -. DR ProteomicsDB; 51809; -. DR Pumba; P05161; -. DR TopDownProteomics; P05161; -. DR Antibodypedia; 809; 623 antibodies from 40 providers. DR DNASU; 9636; -. DR Ensembl; ENST00000649529.1; ENSP00000496832.1; ENSG00000187608.10. DR GeneID; 9636; -. DR KEGG; hsa:9636; -. DR MANE-Select; ENST00000649529.1; ENSP00000496832.1; NM_005101.4; NP_005092.1. DR UCSC; uc001acj.5; human. DR AGR; HGNC:4053; -. DR CTD; 9636; -. DR DisGeNET; 9636; -. DR GeneCards; ISG15; -. DR HGNC; HGNC:4053; ISG15. DR HPA; ENSG00000187608; Tissue enhanced (salivary). DR MalaCards; ISG15; -. DR MIM; 147571; gene. DR MIM; 616126; phenotype. DR neXtProt; NX_P05161; -. DR OpenTargets; ENSG00000187608; -. DR Orphanet; 319563; Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency. DR PharmGKB; PA28465; -. DR VEuPathDB; HostDB:ENSG00000187608; -. DR eggNOG; KOG0001; Eukaryota. DR GeneTree; ENSGT00940000162007; -. DR InParanoid; P05161; -. DR OMA; CTVYMNL; -. DR OrthoDB; 1378884at2759; -. DR PhylomeDB; P05161; -. DR TreeFam; TF338379; -. DR PathwayCommons; P05161; -. DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism. DR Reactome; R-HSA-168276; NS1 Mediated Effects on Host Pathways. DR Reactome; R-HSA-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta. DR Reactome; R-HSA-5656169; Termination of translesion DNA synthesis. DR Reactome; R-HSA-909733; Interferon alpha/beta signaling. DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling. DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; P05161; -. DR BioGRID-ORCS; 9636; 26 hits in 1168 CRISPR screens. DR ChiTaRS; ISG15; human. DR EvolutionaryTrace; P05161; -. DR GeneWiki; ISG15; -. DR GenomeRNAi; 9636; -. DR Pharos; P05161; Tbio. DR PRO; PR:P05161; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P05161; Protein. DR Bgee; ENSG00000187608; Expressed in decidua and 206 other cell types or tissues. DR ExpressionAtlas; P05161; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IC:UniProt. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005178; F:integrin binding; IPI:UniProtKB. DR GO; GO:0031386; F:protein tag activity; IDA:UniProt. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IBA:GO_Central. DR GO; GO:0042742; P:defense response to bacterium; IMP:UniProtKB. DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB. DR GO; GO:0045087; P:innate immune response; IDA:UniProt. DR GO; GO:0007229; P:integrin-mediated signaling pathway; IDA:UniProtKB. DR GO; GO:0032020; P:ISG15-protein conjugation; IDA:UniProtKB. DR GO; GO:0019941; P:modification-dependent protein catabolic process; IBA:GO_Central. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IMP:ARUK-UCL. DR GO; GO:0045071; P:negative regulation of viral genome replication; IDA:UniProtKB. DR GO; GO:0030501; P:positive regulation of bone mineralization; ISS:UniProtKB. DR GO; GO:0045648; P:positive regulation of erythrocyte differentiation; IEA:Ensembl. DR GO; GO:0032728; P:positive regulation of interferon-beta production; IDA:UniProtKB. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IDA:UniProtKB. DR GO; GO:0032461; P:positive regulation of protein oligomerization; IDA:UniProtKB. DR GO; GO:0032729; P:positive regulation of type II interferon production; IDA:UniProtKB. DR GO; GO:0070585; P:protein localization to mitochondrion; IDA:UniProtKB. DR GO; GO:0032649; P:regulation of type II interferon production; IMP:UniProtKB. DR GO; GO:0034340; P:response to type I interferon; IDA:UniProtKB. DR GO; GO:0009615; P:response to virus; IDA:UniProtKB. DR CDD; cd01792; Ubl1_ISG15; 1. DR CDD; cd01810; Ubl2_ISG15; 1. DR InterPro; IPR015496; Ubiquilin. DR InterPro; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR InterPro; IPR019956; Ubiquitin_dom. DR PANTHER; PTHR10677:SF3; FI07626P-RELATED; 1. DR PANTHER; PTHR10677; UBIQUILIN; 1. DR Pfam; PF00240; ubiquitin; 2. DR PRINTS; PR00348; UBIQUITIN. DR SMART; SM00213; UBQ; 2. DR SUPFAM; SSF54236; Ubiquitin-like; 2. DR PROSITE; PS50053; UBIQUITIN_2; 2. DR Genevisible; P05161; HS. PE 1: Evidence at protein level; KW 3D-structure; Antiviral defense; Cytoplasm; Direct protein sequencing; KW Disulfide bond; Host-virus interaction; Immunity; Innate immunity; KW Isopeptide bond; Reference proteome; Repeat; S-nitrosylation; Secreted; KW Ubl conjugation pathway. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:2477469" FT CHAIN 2..157 FT /note="Ubiquitin-like protein ISG15" FT /id="PRO_0000035986" FT PROPEP 158..165 FT /note="Removed in mature form" FT /id="PRO_0000035987" FT DOMAIN 2..78 FT /note="Ubiquitin-like 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT DOMAIN 79..157 FT /note="Ubiquitin-like 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT REGION 153..157 FT /note="Involved in the ligation of specific target FT proteins" FT /evidence="ECO:0000250" FT MOTIF 152..157 FT /note="LRLRGG" FT SITE 153 FT /note="Interacts with activating enzyme" FT /evidence="ECO:0000250" FT MOD_RES 78 FT /note="S-nitrosocysteine; alternate" FT /evidence="ECO:0000269|PubMed:18606809" FT DISULFID 78 FT /note="Interchain (with C-87 in UBE2N); alternate" FT /evidence="ECO:0000269|PubMed:22693631" FT CROSSLNK 157 FT /note="Glycyl lysine isopeptide (Gly-Lys) (interchain with FT K-? in acceptor proteins)" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT VARIANT 83 FT /note="S -> N (in dbSNP:rs1921)" FT /evidence="ECO:0000269|PubMed:15489334, ECO:0000269|Ref.5, FT ECO:0000269|Ref.6" FT /id="VAR_016181" FT MUTAGEN 44 FT /note="R->A: Does not affect ISG15 signaling, interaction FT with ITGAL or activation of SRC family tyrosine kinases." FT /evidence="ECO:0000269|PubMed:29100055" FT MUTAGEN 83 FT /note="S->A: Does not affect ISG15 signaling, interaction FT with ITGAL or activation of SRC family tyrosine kinases." FT /evidence="ECO:0000269|PubMed:29100055" FT MUTAGEN 96 FT /note="Y->L: Reduces ISG15 signaling. Strongly reduces FT ISG15 signaling and abolishes interaction with ITGAL and FT activation of SRC family tyrosine kinases; when associated FT with D-102." FT /evidence="ECO:0000269|PubMed:29100055" FT MUTAGEN 99 FT /note="R->A: Strongly reduces ISG15 signaling and abolishes FT interaction with ITGAL." FT /evidence="ECO:0000269|PubMed:29100055" FT MUTAGEN 101 FT /note="T->A: Strongly reduces ISG15 signaling and abolishes FT interaction with ITGAL and activation of SRC family FT tyrosine kinases." FT /evidence="ECO:0000269|PubMed:29100055" FT MUTAGEN 102 FT /note="Q->D: Reduces ISG15 signaling. Strongly reduces FT ISG15 signaling and abolishes interaction with ITGAL and FT activation of SRC family tyrosine kinases; when associated FT with L-96." FT /evidence="ECO:0000269|PubMed:29100055" FT MUTAGEN 103 FT /note="T->A: Strongly reduces ISG15 signaling and abolishes FT interaction with ITGAL." FT /evidence="ECO:0000269|PubMed:29100055" FT CONFLICT 35 FT /note="K -> N (in Ref. 2; AAA36128)" FT /evidence="ECO:0000305" FT STRAND 4..9 FT /evidence="ECO:0007829|PDB:3RT3" FT STRAND 10..12 FT /evidence="ECO:0007829|PDB:6BI8" FT STRAND 14..18 FT /evidence="ECO:0007829|PDB:3RT3" FT STRAND 20..22 FT /evidence="ECO:0007829|PDB:6BI8" FT HELIX 25..36 FT /evidence="ECO:0007829|PDB:3RT3" FT HELIX 40..42 FT /evidence="ECO:0007829|PDB:3RT3" FT STRAND 43..48 FT /evidence="ECO:0007829|PDB:3RT3" FT STRAND 56..58 FT /evidence="ECO:0007829|PDB:7S6P" FT HELIX 60..63 FT /evidence="ECO:0007829|PDB:3RT3" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:6BI8" FT STRAND 70..75 FT /evidence="ECO:0007829|PDB:3RT3" FT STRAND 82..87 FT /evidence="ECO:0007829|PDB:6FFA" FT STRAND 93..98 FT /evidence="ECO:0007829|PDB:6FFA" FT HELIX 104..115 FT /evidence="ECO:0007829|PDB:6FFA" FT HELIX 119..121 FT /evidence="ECO:0007829|PDB:6FFA" FT STRAND 122..126 FT /evidence="ECO:0007829|PDB:6FFA" FT STRAND 129..131 FT /evidence="ECO:0007829|PDB:5TL6" FT HELIX 137..140 FT /evidence="ECO:0007829|PDB:6FFA" FT STRAND 147..152 FT /evidence="ECO:0007829|PDB:6FFA" SQ SEQUENCE 165 AA; 17888 MW; B6858A15AB0FFFDE CRC64; MGWDLTVKML AGNEFQVSLS SSMSVSELKA QITQKIGVHA FQQRLAVHPS GVALQDRVPL ASQGLGPGST VLLVVDKCDE PLSILVRNNK GRSSTYEVRL TQTVAHLKQQ VSGLEGVQDD LFWLTFEGKP LEDQLPLGEY GLKPLSTVFM NLRLRGGGTE PGGRS //