Abstract
Mammalian cells have developed an elaborate network of immunoproteins that serve to identify and combat viral pathogens. Interferon-stimulated gene 15 (ISG15) is a 15.2 kDa tandem ubiquitin-like protein (UBL) that is used by specific E1–E2–E3 ubiquitin cascade enzymes to interfere with the activity of viral proteins. Recent biochemical studies have demonstrated how the E3 ligase HECT and RCC1-containing protein 5 (HERC5) regulates ISG15 signaling in response to hepatitis C (HCV), influenza-A (IAV), human immunodeficiency virus (HIV), SARS-CoV-2 and other viral infections. Taken together, the potent antiviral activity displayed by HERC5 and ISG15 make them promising drug targets for the development of novel antiviral therapeutics that can augment the host antiviral response. In this review, we examine the emerging role of ISG15 in antiviral immunity with a particular focus on how HERC5 orchestrates the specific and timely ISGylation of viral proteins in response to infection.
Highlights
Viral replication is a highly coordinated process that relies heavily on the host cellular machinery and can disrupt critical cellular activities leading to disease and/or death [1,2,3,4].Viruses exert immense evolutionary pressure on their hosts, driving the development of complex cellular immune responses that work to identify, combat and eliminate infectious pathogens
These findings suggest that NS5A is the primary hepatitis C virus (HCV) target substrate of homologous to E6AP C-terminus (HECT) and regulator of chromatin condensation 1 (RCC1)-containing protein 5 (HERC5)-dependent
HERC5 ISGylation activity results in a pro- or anti-virulent response to HCV infection, and whether HERC5 is necessary for catalyzing the modes of Interferon-stimulated gene 15 (ISG15) inhibition that have been observed for HCV NS5A proteins
Summary
Viral replication is a highly coordinated process that relies heavily on the host cellular machinery and can disrupt critical cellular activities leading to disease and/or death [1,2,3,4]. When cells detect a viral pathogen, specific PRRs become activated that signal for mitochondrial antiviral signaling (MAVS) proteins to upregulate interferon-α/β (IFN-α/β) cytokine production [2,7,8,9]. Viruses 2021, 13, 1102 phosphorylated STAT1 and STAT2 proteins form a ternary complex with methylated interferon regulatory interferon regulatoryfactor factor9 9(IRF9),. HERC5 plays a central role in mam(ISG15) are two antiviral immune proteins that are induced following IFN-α/β signal malian innate Multiple immunitystudies by ISGylating viral proteins to disrupt viral replication transduction. Recent studies have shown that ISG15, UBE1L, UBE2L6 and HERC5 are tightly regulated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)–an immunological protein complex that is involved in controlling diverse cellular responses to viral infection including cytokine production, DNA transcriptional regulation and interferon activation [33]
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