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Gene Review

ISG15  -  ISG15 ubiquitin-like modifier

Homo sapiens

Synonyms: G1P2, IFI15, IMD38, IP17, Interferon-induced 15 kDa protein, ...
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Disease relevance of ISG15

  • Influenza A virus employs a different strategy: its NS1 protein does not bind the ISG15 protein, but little or no ISG15 protein is produced during infection [1].
  • Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15 [2].
  • Elimination of ISG15 expression by small interfering RNA reversed the IFN-mediated inhibition of HIV-1 replication and release of virions [2].
  • It is likely that ISG15 conjugation plays an important role in antiviral response because a human virus, influenza B virus, inhibits ISG15 conjugation [3].
  • Most importantly, strong cytoplasmic expression of ISG15 was detected by immunohistochemistry in the original tumor specimen from which the melanoma cell lines under investigation were derived [4].

High impact information on ISG15

  • Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection [5].
  • This report provides the first direct evidence that the ISG15 protease UBP43 and possibly protein ISGylation have a role in innate immunity against viral infection [5].
  • Furthermore, restoration of ISG15 conjugation in protein ISGylation-defective K562 cells increases IFN-stimulated promoter activity [6].
  • We identify UBE1L as the E1 enzyme that catalyzes the first activation step in the conjugation of ISG15, and show that the NS1B protein inhibits this activation step in vitro [1].
  • The increased susceptibility of ISG15(-/-) mice to Sindbis virus infection was rescued by expressing wild-type ISG15, but not a mutant form of ISG15 that cannot form conjugates, from the Sindbis virus genome [7].

Biological context of ISG15

  • Moreover, siRNA-mediated down-regulation of the major E2 for ISG15 (UbcH8), which blocked the formation of ISG15 protein conjugates, also increased the levels of polyubiquitinated proteins [8].
  • Here we show that PU.1, an ETS member essential for myeloid/lymphoid cell differentiation, forms heterocomplexes with the immune-restricted IRFs, IRF-8\/ICSBP and IRF-4, which lead to transcriptional activation of ISG15 [9].
  • To investigate the regulation of this posttranslational modification pathway by a genotoxic chemotherapeutic agent, we examined ISG15 induction and conjugation in cells treated with the topoisomerase I (topoI) poison, camptothecin (CPT) [10].
  • We determined that the Lys136 residue near the catalytic site Cys131 is the ISG15 conjugation site in UbcH6 [11].
  • By extensive point mutagenesis of the ISREs from two IFN-stimulated promoters (ISG54 and ISG15), we demonstrate that the B2 and B3 complexes are formed by factors binding to the same DNA sequence [12].

Anatomical context of ISG15


Associations of ISG15 with chemical compounds

  • This study reports that conjugation of the ubiquitin-like species, interferon-stimulated gene, 15-kDa protein (ISG15), also occurs during RA-induced APL differentiation [15].
  • This required the conserved diglycine motif in the carboxyl terminus of ISG15 [15].
  • Recombinant full-length ISG15 has been produced for the first time in high yield by mutating Cys78 to stabilize the protein and by cloning in a C-terminal arginine cap to protect the C terminus against proteolytic inactivation [16].
  • ISG15 is one of the most strongly induced genes upon viral infection, type I interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation [6].
  • The antiviral effect of PLSCR1 correlated with increased expression of a subset of IFN-stimulated genes (ISGs), including ISG15, ISG54, p56, and guanylate binding proteins [17].

Physical interactions of ISG15

  • IRF-3 was originally identified as a member of the IRF family based on homology with other IRF family members and on binding to the ISRE of the ISG15 promoter [18].

Regulatory relationships of ISG15

  • Here, we show that Ubp43 negatively regulates IFN signaling independent of its isopeptidase activity towards ISG15 [19].
  • The C-terminal domain of ISG15 was superimposed on the structure of Nedd8 (r.m.s.d. = 0.84 A) bound to its AppBp1-Uba3 activating enzyme to model ISG15 binding to UbE1L [16].
  • In cytotoxicity assays, ISG15 was a potent inducer of cytolytic activity directed against both K562 (100 lytic units per 10(6) cells) and Daudi (80 lytic units per 10(6) cells) tumor cell targets, indicating that ISG15 enhanced lymphokine-
  • activated killer-like activity [14].
  • Overexpression of IRF-3 stimulates expression of the IFN-stimulated gene 15 (ISG15) promoter, an ISRE-containing promoter [20].
  • We conclude that orally administered IFN-alpha exerts its immunomodulatory effects in humans in part by upregulating the production of ISG-15 by BEC, thereby enhancing the immune reactivity of mucosa-associated lymphocytes [21].

Other interactions of ISG15

  • Since ISG15 was secreted in response to IFN treatment in vitro, its levels in the serum of healthy human volunteers treated with IFN-beta(ser) were quantitated by asymmetric sandwich ELISA [13].
  • Eight of these proteins were subjected to further analysis and verified to be ISG15 modified in IFN-beta-treated cells, increasing the likelihood that most, if not all, targets identified by mass spectroscopy are bona fide ISG15 targets [3].
  • Furthermore, these results raise the possibility that the ISG15 conjugation pathway might use UbcH8-competent Ub ligases in vivo [22].
  • ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form thioester bond with ubiquitin [23].
  • Although the E1 enzyme for ISG15 (Ube1L/E1(ISG15)) has been identified, the identities of the downstream components of the ISG15 conjugation cascade have remained elusive [22].

Analytical, diagnostic and therapeutic context of ISG15


  1. Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein. Yuan, W., Krug, R.M. EMBO J. (2001) [Pubmed]
  2. Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15. Okumura, A., Lu, G., Pitha-Rowe, I., Pitha, P.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Zhao, C., Denison, C., Huibregtse, J.M., Gygi, S., Krug, R.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells. Padovan, E., Terracciano, L., Certa, U., Jacobs, B., Reschner, A., Bolli, M., Spagnoli, G.C., Borden, E.C., Heberer, M. Cancer Res. (2002) [Pubmed]
  5. Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection. Ritchie, K.J., Hahn, C.S., Kim, K.I., Yan, M., Rosario, D., Li, L., de la Torre, J.C., Zhang, D.E. Nat. Med. (2004) [Pubmed]
  6. Protein ISGylation modulates the JAK-STAT signaling pathway. Malakhova, O.A., Yan, M., Malakhov, M.P., Yuan, Y., Ritchie, K.J., Kim, K.I., Peterson, L.F., Shuai, K., Zhang, D.E. Genes Dev. (2003) [Pubmed]
  7. From the cover: IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Lenschow, D.J., Lai, C., Frias-Staheli, N., Giannakopoulos, N.V., Lutz, A., Wolff, T., Osiak, A., Levine, B., Schmidt, R.E., García-Sastre, A., Leib, D.A., Pekosz, A., Knobeloch, K.P., Horak, I., Virgin, H.W. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  8. Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway. Desai, S.D., Haas, A.L., Wood, L.M., Tsai, Y.C., Pestka, S., Rubin, E.H., Saleem, A., Nur-E-Kamal, A., Liu, L.F. Cancer Res. (2006) [Pubmed]
  9. IFN-stimulated gene 15 is synergistically activated through interactions between the myelocyte/lymphocyte-specific transcription factors, PU.1, IFN regulatory factor-8/IFN consensus sequence binding protein, and IFN regulatory factor-4: characterization of a new subtype of IFN-stimulated response element. Meraro, D., Gleit-Kielmanowicz, M., Hauser, H., Levi, B.Z. J. Immunol. (2002) [Pubmed]
  10. Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon. Liu, M., Hummer, B.T., Li, X., Hassel, B.A. J. Interferon Cytokine Res. (2004) [Pubmed]
  11. Link between the Ubiquitin Conjugation System and the ISG15 Conjugation System: ISG15 Conjugation to the UbcH6 Ubiquitin E2 Enzyme. Takeuchi, T., Iwahara, S., Saeki, Y., Sasajima, H., Yokosawa, H. J. Biochem. (2005) [Pubmed]
  12. Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes. Kessler, D.S., Levy, D.E., Darnell, J.E. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  13. In vitro and in vivo secretion of human ISG15, an IFN-induced immunomodulatory cytokine. D'Cunha, J., Ramanujam, S., Wagner, R.J., Witt, P.L., Knight, E., Borden, E.C. J. Immunol. (1996) [Pubmed]
  14. Immunoregulatory properties of ISG15, an interferon-induced cytokine. D'Cunha, J., Knight, E., Haas, A.L., Truitt, R.L., Borden, E.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  15. Involvement of UBE1L in ISG15 conjugation during retinoid-induced differentiation of acute promyelocytic leukemia. Pitha-Rowe, I., Hassel, B.A., Dmitrovsky, E. J. Biol. Chem. (2004) [Pubmed]
  16. Crystal structure of the interferon-induced ubiquitin-like protein ISG15. Narasimhan, J., Wang, M., Fu, Z., Klein, J.M., Haas, A.L., Kim, J.J. J. Biol. Chem. (2005) [Pubmed]
  17. Phospholipid scramblase 1 potentiates the antiviral activity of interferon. Dong, B., Zhou, Q., Zhao, J., Zhou, A., Harty, R.N., Bose, S., Banerjee, A., Slee, R., Guenther, J., Williams, B.R., Wiedmer, T., Sims, P.J., Silverman, R.H. J. Virol. (2004) [Pubmed]
  18. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Lin, R., Heylbroeck, C., Pitha, P.M., Hiscott, J. Mol. Cell. Biol. (1998) [Pubmed]
  19. UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. Malakhova, O.A., Kim, K.I., Luo, J.K., Zou, W., Kumar, K.G., Fuchs, S.Y., Shuai, K., Zhang, D.E. EMBO J. (2006) [Pubmed]
  20. Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes. Au, W.C., Moore, P.A., Lowther, W., Juang, Y.T., Pitha, P.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  21. Oral use of interferon-alpha stimulates ISG-15 transcription and production by human buccal epithelial cells. Smith, J.K., Siddiqui, A.A., Krishnaswamy, G.A., Dykes, R., Berk, S.L., Magee, M., Joyner, W., Cummins, J. J. Interferon Cytokine Res. (1999) [Pubmed]
  22. The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein. Zhao, C., Beaudenon, S.L., Kelley, M.L., Waddell, M.B., Yuan, W., Schulman, B.A., Huibregtse, J.M., Krug, R.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  23. ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form thioester bond with ubiquitin. Zou, W., Papov, V., Malakhova, O., Kim, K.I., Dao, C., Li, J., Zhang, D.E. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  24. High-throughput immunoblotting. Ubiquitiin-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. (2003) [Pubmed]
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