The ISG15 Conjugation System Broadly Targets Newly Synthesized Proteins: Implications for the Antiviral Function of ISG15

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Jun 15

PMID 20542004

Citations 211

Authors

Larissa A Durfee

Nancy Lyon

Kyungwoon Seo

Jon M Huibregtse

Affiliations

Soon will be listed here.

Abstract

ISG15 is an interferon-induced and antiviral ubiquitin-like protein (Ubl). Herc5, the major E3 enzyme for ISG15, mediates the ISGylation of more than 300 proteins in interferon-stimulated cells. In addressing this broad substrate selectivity of Herc5, we found that: (1) the range of substrates extends even further and includes many exogenously expressed foreign proteins, (2) ISG15 conjugation is restricted to newly synthesized pools of proteins, and (3) Herc5 is physically associated with polyribosomes. These results lead to a model for ISGylation in which Herc5 broadly modifies newly synthesized proteins in a cotranslational manner. This further suggests that, in the context of an interferon-stimulated cell, newly translated viral proteins may be primary targets of ISG15. Consistent with this, we demonstrate that ISGylation of human papillomavirus (HPV) L1 capsid protein has a dominant-inhibitory effect on the infectivity of HPV16 pseudoviruses.

Citing Articles

Site-selective photo-crosslinking for the characterisation of transient ubiquitin-like protein-protein interactions.

Sandy Z, Wang Z, Behera D, Foster B, Martin F, Bruninghoff K PLoS One. 2025; 20(1):e0316321.

PMID: 39869599 PMC: 11771908. DOI: 10.1371/journal.pone.0316321.

Distinct interactomes of ADAR1 nuclear and cytoplasmic protein isoforms and their responses to interferon induction.

Vukic D, Cherian A, Keskitalo S, Bong Y, Maronek M, Yadav L Nucleic Acids Res. 2024; 52(22):14184-14204.

PMID: 39673305 PMC: 11662693. DOI: 10.1093/nar/gkae1106.

Suppression of SARS-CoV-2 nucleocapsid protein dimerization by ISGylation and its counteraction by viral PLpro.

Bang W, Kim J, Seo K, Lee J, Han J, Park D Front Microbiol. 2024; 15:1490944.

PMID: 39512937 PMC: 11540652. DOI: 10.3389/fmicb.2024.1490944.

RAPIDASH: Tag-free enrichment of ribosome-associated proteins reveals composition dynamics in embryonic tissue, cancer cells, and macrophages.

Susanto T, Hung V, Levine A, Chen Y, Kerr C, Yoo Y Mol Cell. 2024; 84(18):3545-3563.e25.

PMID: 39260367 PMC: 11460945. DOI: 10.1016/j.molcel.2024.08.023.

ISGylation of the SARS-CoV-2 N protein by HERC5 impedes N oligomerization and thereby viral RNA synthesis.

Zhu J, Liu G, Sayyad Z, Goins C, Stauffer S, Gack M J Virol. 2024; 98(9):e0086924.

PMID: 39194248 PMC: 11406920. DOI: 10.1128/jvi.00869-24.

References

Takeuchi T, Inoue S, Yokosawa H . Identification and Herc5-mediated ISGylation of novel target proteins. Biochem Biophys Res Commun. 2006; 348(2):473-7. DOI: 10.1016/j.bbrc.2006.07.076. View

Barnard P, McMillan N . The human papillomavirus E7 oncoprotein abrogates signaling mediated by interferon-alpha. Virology. 1999; 259(2):305-13. DOI: 10.1006/viro.1999.9771. View

Buck C, Thompson C . Production of papillomavirus-based gene transfer vectors. Curr Protoc Cell Biol. 2008; Chapter 26:Unit 26.1. DOI: 10.1002/0471143030.cb2601s37. View

Vetro J, Chang Y . Yeast methionine aminopeptidase type 1 is ribosome-associated and requires its N-terminal zinc finger domain for normal function in vivo. J Cell Biochem. 2002; 85(4):678-88. DOI: 10.1002/jcb.10161. View

Lindner H, Lytvyn V, Qi H, Lachance P, Ziomek E, Menard R . Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys. 2007; 466(1):8-14. PMC: 7094341. DOI: 10.1016/j.abb.2007.07.006. View

Lee S, Harris J, Swanstrom R . A strongly transdominant mutation in the human immunodeficiency virus type 1 gag gene defines an Achilles heel in the virus life cycle. J Virol. 2009; 83(17):8536-43. PMC: 2738153. DOI: 10.1128/JVI.00317-09. View

Jeon Y, Choi J, Lee J, Yu K, Kim S, Ka S . ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathway. EMBO Rep. 2009; 10(4):374-80. PMC: 2672892. DOI: 10.1038/embor.2009.23. View

Slade H, Owens M, Tomai M, Miller R . Imiquimod 5% cream (Aldara). Expert Opin Investig Drugs. 2005; 7(3):437-49. DOI: 10.1517/13543784.7.3.437. View

Huang J, Liang Z, Yang B, Tian H, Ma J, Zhang H . Derepression of microRNA-mediated protein translation inhibition by apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) and its family members. J Biol Chem. 2007; 282(46):33632-33640. DOI: 10.1074/jbc.M705116200. View

10.

Durfee L, Kelley M, Huibregtse J . The basis for selective E1-E2 interactions in the ISG15 conjugation system. J Biol Chem. 2008; 283(35):23895-902. PMC: 2527107. DOI: 10.1074/jbc.M804069200. View

11.

Zou W, Papov V, Malakhova O, Kim K, Dao C, Li J . ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form thioester bond with ubiquitin. Biochem Biophys Res Commun. 2005; 336(1):61-8. DOI: 10.1016/j.bbrc.2005.08.038. View

12.

Hochrainer K, Mayer H, Baranyi U, Binder B, Lipp J, Kroismayr R . The human HERC family of ubiquitin ligases: novel members, genomic organization, expression profiling, and evolutionary aspects. Genomics. 2005; 85(2):153-64. DOI: 10.1016/j.ygeno.2004.10.006. View

13.

Ullers R, Luirink J, Harms N, Schwager F, Georgopoulos C, Genevaux P . SecB is a bona fide generalized chaperone in Escherichia coli. Proc Natl Acad Sci U S A. 2004; 101(20):7583-8. PMC: 419649. DOI: 10.1073/pnas.0402398101. View

14.

Lenschow D, Giannakopoulos N, Gunn L, Johnston C, OGuin A, Schmidt R . Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005; 79(22):13974-83. PMC: 1280211. DOI: 10.1128/JVI.79.22.13974-13983.2005. View

15.

Ronco L, Karpova A, Vidal M, Howley P . Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev. 1998; 12(13):2061-72. PMC: 316980. DOI: 10.1101/gad.12.13.2061. View

16.

Wong J, Pung Y, Sze N, Chin K . 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; 103(28):10735-40. PMC: 1484417. DOI: 10.1073/pnas.0600397103. View

17.

Chang Y, Yan X, Xie Y, Gao X, Song A, Zhang D . Different roles for two ubiquitin-like domains of ISG15 in protein modification. J Biol Chem. 2008; 283(19):13370-7. DOI: 10.1074/jbc.M800162200. View

18.

Zhao C, Denison C, Huibregtse J, Gygi S, Krug R . Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005; 102(29):10200-5. PMC: 1177427. DOI: 10.1073/pnas.0504754102. View

19.

Hadjebi O, Casas-Terradellas E, Garcia-Gonzalo F, Rosa J . The RCC1 superfamily: from genes, to function, to disease. Biochim Biophys Acta. 2008; 1783(8):1467-79. DOI: 10.1016/j.bbamcr.2008.03.015. View

20.

Giannakopoulos N, Arutyunova E, Lai C, Lenschow D, Haas A, Virgin H . ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. J Virol. 2008; 83(4):1602-10. PMC: 2643764. DOI: 10.1128/JVI.01590-08. View