Abstract
The ubiquitin proteasome system (UPS) is a protein degradation machinery that is crucial for cellular homeostasis in eukaryotes. Therefore, it is not surprising that the UPS coordinates almost all host cellular processes, including host–pathogen interactions. This protein degradation machinery acts predominantly by tagging substrate proteins designated for degradation with a ubiquitin molecule. These ubiquitin tags have been involved at various steps of the innate immune response. Hence, herpesviruses have evolved ways to antagonize the host defense mechanisms by targeting UPS components such as ubiquitin E3 ligases and deubiquitinases (DUBs) that establish a productive infection. This review delineates how herpesviruses usurp the critical roles of ubiquitin E3 ligases and DUBs in innate immune response to escape host-antiviral immune response, with particular focus on retinoic acid-inducible gene I (RIG-I)-like receptors (RLR), cyclic-GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon (IFN) genes (STING) pathways, and inflammasome signaling.
Highlights
The Herpesviridae are a family of large viruses that contain double-stranded DNA genomes and ubiquitously cause a range of human diseases of varying levels of severity [1].They are classified into α, β, and γ-Herpesvirinae [2]
Mounting data have shed more light on the underlying molecular mechanisms of the virus-host standoff in innate immune responses. This innate immune response is often initiated by pathogen recognition receptors (PRRs) that sense evolutionarily conserved molecular patterns of the pathogens, termed pathogen-associated molecular patterns (PAMPs) [5]
Qin et al reported that activation of RNF26mediated type I IFN regulation is temporal by two independent mechanisms; RNF26 interacts with stimulator of interferon (IFN) genes (STING) to stabilize it during the early phase of viral infection, while RNF26 later binds to IRF3 for downregulation of IFN-mediated signaling by autophagy-associated degradation
Summary
The Herpesviridae are a family of large viruses that contain double-stranded DNA genomes and ubiquitously cause a range of human diseases of varying levels of severity [1]. Four types of PRRs have been reported; the Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), and cytosolic viral DNA sensors such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) [6,7,8,9,10] These different PRRs elicit intracellular signaling cascades that activate type I interferon (IFN) and pro-inflammatory cytokines, resulting in induction of innate immune response to eradicate the pathogen [11]. Ubiquitination and deubiquitination should be tightly controlled to fine-tune several cellular responses, including innate immune responses In line with this point of view, herpesviruses have evolved ways to antagonize the host defense mechanisms by targeting ubiquitin E3 ligases and DUBs in order to minimize the host antiviral responses for establishment of productive infection [23]. We would highlight the viral counteractions in the RLR, cGAS-STING pathways, and inflammasome signaling, but not in TLR pathway which is already highlighted in other papers
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