8y4z

Structural highlights

Function

HERC5_HUMAN Major E3 ligase for ISG15 conjugation (PubMed:26355087, PubMed:27564865, PubMed:27534820, PubMed:34572049, PubMed:37279284). Acts as a positive regulator of innate antiviral response in cells induced by interferon. Functions as part of the ISGylation machinery that recognizes target proteins in a broad and relatively non-specific manner. Catalyzes ISGylation of IRF3 which results in sustained activation, it attenuates IRF3-PIN1 interaction, which antagonizes IRF3 ubiquitination and degradation, and boosts the antiviral response. Mediates ISGylation of the phosphatase PTEN leading to its degradation, thus alleviating its suppression of the PI3K-AKT signaling pathway and promoting the production of cytokines that facilitate bacterial clearance (PubMed:37279284). Interferes with the function of key viral structural proteins such as ebolavirus structural protein VP40 or HIV-1 protein GAG (PubMed:22093708, PubMed:34572049). Catalyzes ISGylation of influenza A viral NS1 which attenuates virulence; ISGylated NS1 fails to form homodimers and thus to interact with its RNA targets. Catalyzes ISGylation of papillomavirus type 16 L1 protein which results in dominant-negative effect on virus infectivity. Physically associated with polyribosomes, broadly modifies newly synthesized proteins in a cotranslational manner. In an interferon-stimulated cell, newly translated viral proteins are primary targets of ISG15. Promotes parkin/PRKN ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation (PubMed:27534820).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]} (Microbial infection) Functions as an E3 ligase for ISGylation of hepatitis B virus protein X leading to enhanced viral replication due to increased interferon resistance.^[14]

References

1. ↑ Dastur A, Beaudenon S, Kelley M, Krug RM, Huibregtse JM. Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells. J Biol Chem. 2006 Feb 17;281(7):4334-8. PMID:16407192 doi:10.1074/jbc.M512830200
2. ↑ Wong JJ, Pung YF, Sze NS, Chin KC. HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets. Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10735-40. PMID:16815975 doi:10.1073/pnas.0600397103
3. ↑ Takeuchi T, Inoue S, Yokosawa H. Identification and Herc5-mediated ISGylation of novel target proteins. Biochem Biophys Res Commun. 2006 Sep 22;348(2):473-7. PMID:16884686 doi:10.1016/j.bbrc.2006.07.076
4. ↑ Zhao C, Hsiang TY, Kuo RL, Krug RM. ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2253-8. PMID:20133869 doi:10.1073/pnas.0909144107
5. ↑ Shi HX, Yang K, Liu X, Liu XY, Wei B, Shan YF, Zhu LH, Wang C. Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol Cell Biol. 2010 May;30(10):2424-36. PMID:20308324 doi:10.1128/MCB.01466-09
6. ↑ Tang Y, Zhong G, Zhu L, Liu X, Shan Y, Feng H, Bu Z, Chen H, Wang C. Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1 protein. J Immunol. 2010 May 15;184(10):5777-90. PMID:20385878 doi:10.4049/jimmunol.0903588
7. ↑ Durfee LA, Lyon N, Seo K, Huibregtse JM. The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15. Mol Cell. 2010 Jun 11;38(5):722-32. PMID:20542004 doi:10.1016/j.molcel.2010.05.002
8. ↑ Woods MW, Kelly JN, Hattlmann CJ, Tong JG, Xu LS, Coleman MD, Quest GR, Smiley JR, Barr SD. Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag. Retrovirology. 2011 Nov 17;8:95. PMID:22093708 doi:10.1186/1742-4690-8-95
9. ↑ Jacobs SR, Stopford CM, West JA, Bennett CL, Giffin L, Damania B. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 1 Interacts with a Member of the Interferon-Stimulated Gene 15 Pathway. J Virol. 2015 Nov;89(22):11572-83. PMID:26355087 doi:10.1128/JVI.01482-15
10. ↑ Im E, Yoo L, Hyun M, Shin WH, Chung KC. Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin. Open Biol. 2016 Aug;6(8):160193. PMID:27534820 doi:10.1098/rsob.160193
11. ↑ Kim YJ, Kim ET, Kim YE, Lee MK, Kwon KM, Kim KI, Stamminger T, Ahn JH. Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators. PLoS Pathog. 2016 Aug 26;12(8):e1005850. PMID:27564865 doi:10.1371/journal.ppat.1005850
12. ↑ Paparisto E, Hunt NR, Labach DS, Coleman MD, Di Gravio EJ, Dodge MJ, Friesen NJ, Côté M, Müller A, Hoenen T, Barr SD. Interferon-Induced HERC5 Inhibits Ebola Virus Particle Production and Is Antagonized by Ebola Glycoprotein. Cells. 2021 Sep 13;10(9):2399. PMID:34572049 doi:10.3390/cells10092399
13. ↑ Du X, Sheng J, Chen Y, He S, Yang Y, Huang Y, Fu Y, Lie L, Han Z, Zhu B, Liu H, Wen Q, Zhou X, Zhou C, Hu S, Ma L. The E3 ligase HERC5 promotes antimycobacterial responses in macrophages by ISGylating the phosphatase PTEN. Sci Signal. 2023 Jun 6;16(788):eabm1756. PMID:37279284 doi:10.1126/scisignal.abm1756
14. ↑ Bawono RG, Abe T, Qu M, Kuroki D, Deng L, Matsui C, Ryo A, Suzuki T, Matsuura Y, Sugiyama M, Mizokami M, Shimotohno K, Shoji I. HERC5 E3 ligase mediates ISGylation of hepatitis B virus X protein to promote viral replication. J Gen Virol. 2021 Oct;102(10). PMID:34661519 doi:10.1099/jgv.0.001668