5chw

Structural highlights

Function

[ISG15_MOUSE] 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.^{[1] [2] [3] [4] [5] [6] [7] [8]}

References

1. ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
2. ↑ Zou W, Wang J, Zhang DE. Negative regulation of ISG15 E3 ligase EFP through its autoISGylation. Biochem Biophys Res Commun. 2007 Mar 2;354(1):321-7. Epub 2007 Jan 8. PMID:17222803 doi:http://dx.doi.org/10.1016/j.bbrc.2006.12.210
3. ↑ Lenschow DJ, Lai C, Frias-Staheli N, Giannakopoulos NV, Lutz A, Wolff T, Osiak A, Levine B, Schmidt RE, Garcia-Sastre A, Leib DA, Pekosz A, Knobeloch KP, Horak I, Virgin HW 4th. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1371-6. Epub 2007 Jan 16. PMID:17227866 doi:http://dx.doi.org/10.1073/pnas.0607038104
4. ↑ Okumura F, Zou W, Zhang DE. ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP. Genes Dev. 2007 Feb 1;21(3):255-60. PMID:17289916 doi:http://dx.doi.org/10.1101/gad.1521607
5. ↑ Kim MJ, Hwang SY, Imaizumi T, Yoo JY. Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J Virol. 2008 Feb;82(3):1474-83. Epub 2007 Dec 5. PMID:18057259 doi:http://dx.doi.org/10.1128/JVI.01650-07
6. ↑ Maragno AL, Pironin M, Alcalde H, Cong X, Knobeloch KP, Tangy F, Zhang DE, Ghysdael J, Quang CT. ISG15 modulates development of the erythroid lineage. PLoS One. 2011;6(10):e26068. doi: 10.1371/journal.pone.0026068. Epub 2011 Oct 12. PMID:22022510 doi:http://dx.doi.org/10.1371/journal.pone.0026068
7. ↑ Werneke SW, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Vanlandingham DL, Higgs S, Fontanet A, Albert ML, Lenschow DJ. ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathog. 2011 Oct;7(10):e1002322. doi: 10.1371/journal.ppat.1002322. Epub, 2011 Oct 20. PMID:22028657 doi:http://dx.doi.org/10.1371/journal.ppat.1002322
8. ↑ Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, Mansouri D, Salem S, Radovanovic I, Grant AV, Adimi P, Mansouri N, Okada S, Bryant VL, Kong XF, Kreins A, Velez MM, Boisson B, Khalilzadeh S, Ozcelik U, Darazam IA, Schoggins JW, Rice CM, Al-Muhsen S, Behr M, Vogt G, Puel A, Bustamante J, Gros P, Huibregtse JM, Abel L, Boisson-Dupuis S, Casanova JL. Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science. 2012 Sep 28;337(6102):1684-8. Epub 2012 Aug 2. PMID:22859821 doi:http://dx.doi.org/10.1126/science.1224026