ISGylation in Innate Antiviral Immunity and Pathogen Defense Responses: A Review.

Mengdi Zhang,Haiyan Yan,Fangwei Wang,Ting Liu,Jingxian Li,Linghui Zeng,Jun Huang,Fangfang Zhou

doi:10.3389/fcell.2021.788410

Abstract

The interferon-stimulating gene 15 (ISG15) protein is a ubiquitin-like protein induced by interferons or pathogens. ISG15 can exist in free form or covalently bind to the target protein through an enzymatic cascade reaction, which is called ISGylation. ISGylation has been found to play an important role in the innate immune responses induced by type I interferon, and is, thus, critical for the defense of host cells against RNA, DNA, and retroviruses. Through covalent binding with the host and viral target proteins, ISG15 inhibits the release of viral particles, hinder viral replication, and regulates the incubation period of viruses, thereby exerting strong antiviral effects. The SARS-CoV-2 papain-like protease, a virus-encoded deubiquitinating enzyme, has demonstrated activity on both ubiquitin and ISG15 chain conjugations, thus playing a suppressive role against the host antiviral innate immune response. Here we review the recent research progress in understanding ISG15-type ubiquitin-like modifications, with an emphasis on the underlying molecular mechanisms. We provide comprehensive references for further studies on the role of ISG15 in antiviral immunity, which may enable development of new antiviral drugs.

Highlights

Interferon-stimulated gene 15 (ISG15) is a member of the family of interferon-stimulating genes (ISGs) (Takeuchi et al, 2019), which are fast and strong type I interferon (IFN)-stimulated reaction proteins that inhibit viral replication, whose function against virus invasion has been fully investigated (Loeb and Haas, 1992; Hermann and Bogunovic, 2017; Sooryanarain et al, 2017)
Proteomic studies have identified that the immuneregulating factors interferon-regulated transcription factor 3 (IRF3), STAT1, and Janus kinase one function as substrates of ISG15 and that the ISGylation of these proteins increases the release of type I IFNs and ISGs, thereby extending the immune response signal cascade (Ganesan et al, 2016; Albert et al, 2018; Yoo et al, 2018; Malakhov et al, 2003)
ISG15 inhibits viral proteins nuclear translocation and restores host antiviral responses ISGylation of NPs inhibit the oligomerization of unmodified NPs, which impedes viral RNA synthesis ISG15 inhibits its protease activity to restore host protein translation ISG15 inhibits the monoubiquitination of Gag protein and block its interaction with TSG101 ISGylation of NEDD4 ubiquitin-binding enzyme inhibits its interaction with VP40 The ISGylation of charged multivesicular body protein 5 (CHMP5) limits the membrane recruitment of Vps4 and its interaction with the ASLV Gag PLpro protease is a virus-encoded DUB, which active on ubiquitin like molecule ISG15

Summary

Introduction

Interferon-stimulated gene 15 (ISG15) is a member of the family of interferon-stimulating genes (ISGs) (Takeuchi et al, 2019), which are fast and strong type I interferon (IFN)-stimulated reaction proteins that inhibit viral replication, whose function against virus invasion has been fully investigated (Loeb and Haas, 1992; Hermann and Bogunovic, 2017; Sooryanarain et al, 2017). The free form of ISG15 binds to the LFA1 receptor on the surface of NK cells and T lymphocytes, increasing the release of type I and II IFNs and activating natural and acquired immunity

Results

Conclusion