Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity

Zhu, Xinyu; Chen, Jiyao; Tian, Liyuan; Zhou, Yanrong; Xu, Shangen; Long, Siwen; Wang, Dan; Fang, Liurong; Xiao, Shaobo

doi:10.1128/jvi.02162-19

Cited by 32 publications

(31 citation statements)

References 75 publications

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“…In addition, ORF7b and the short ORF3b are intriguing hits because both are accessory proteins that have been reported to either activate the kinase p38 (an inducer of PB disassembly) or antagonize IFN responses (53,80). Not picked up in our screen, the viral 3C-like protease, nsp5, is also of particular interest because porcine CoV nsp5 cleaves Dcp1a, an event that would be predicted to cause PB disassembly (81). Although nsp6 and nsp11 were top hits in our unthresholded PB screen (Fig 1), their expression is either toxic or difficult to detect and we are engaged in developing strategies to minimize these issues and study them further.…”

Section: Discussionmentioning

confidence: 99%

Human coronaviruses disassemble processing bodies

Robinson

Kleer

Mulloy

et al. 2020

Preprint

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The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease of 2019 (COVID-19). The host response to CoV infection is complex and regulated, in part, by intracellular antiviral signaling pathways triggered in the first cells that are infected. Emerging evidence suggests that CoVs hijack these antiviral responses to reshape the production of interferons and proinflammatory cytokines. Processing bodies (PBs) are membraneless ribonucleoprotein granules that mediate decay or translational suppression of cellular mRNAs; this is particularly relevant for proinflammatory cytokine mRNA which normally reside in PBs and are repressed. Emerging evidence also suggests that PBs or their components play important direct-acting antiviral roles, providing a compelling reason for their frequent disassembly by many viruses. No information is known about how human CoVs impact PBs. Here, we provide data to show that infection with the human CoV, OC43, causes PB disassembly. Moreover, we show that several SARS-CoV-2 gene products also mediate PB loss and virus-induced PB loss correlates with elevated levels of proinflammatory cytokine mRNAs that would normally be repressed in PBs. Finally, we demonstrate that stimulating PB formation prior to OC43 infection restricts viral replication. These data suggest that SARS-CoV-2 and other CoVs disassemble PBs during infection to support viral replication and evade innate immune responses. As an unintended side effect, the disassembly of PBs enhances translation of proinflammatory cytokine mRNAs which normally reside in PBs, thereby reshaping the subsequent immune response.

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Section: Discussionmentioning

confidence: 99%

Human coronaviruses disassemble processing bodies

Robinson

Kleer

Mulloy

et al. 2020

Preprint

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“…For example, NSP5 of feline infectious peritonitis virus, which is an alphacoronavirus, is capable of suppressing type I IFN expression through cleavage of IKK-γ [26]. NSP5 of porcine deltacoronavirus antagonizes type I IFN signaling through cleavage of STAT2 and DCP1A, which is an ISG with antiviral activity [27,28]. Generally in line with this, cysteine protease activity of SARS-CoV-2 NSP5 is required for the induction of pro-inflammatory response through cleavage of the NLRP12 suppressor of cytokine signaling [16].…”

Section: Ivyspringmentioning

confidence: 99%

SARS-CoV-2 main protease suppresses type I interferon production by preventing nuclear translocation of phosphorylated IRF3

et al. 2021

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Suppression of type I interferon (IFN) response is one pathological outcome of the infection of highly pathogenic human coronaviruses. To effect this, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 encode multiple IFN antagonists. In this study, we reported on the IFN antagonism of SARS-CoV-2 main protease NSP5. NSP5 proteins of both SARS-CoV and SARS-CoV-2 counteracted Sendai virus-induced IFN production. NSP5 variants G15S and K90R commonly seen in circulating strains of SARS-CoV-2 retained the IFN-antagonizing property. The suppressive effect of NSP5 on IFN-β gene transcription induced by RIG-I, MAVS, TBK1 and IKKϵ suggested that NSP5 likely acts at a step downstream of IRF3 phosphorylation in the cytoplasm. NSP5 did not influence steady-state expression or phosphorylation of IRF3, suggesting that IRF3, regardless of its phosphorylation state, might not be the substrate of NSP5 protease. However, nuclear translocation of phosphorylated IRF3 was severely compromised in NSP5-expressing cells. Taken together, our work revealed a new mechanism by which NSP5 proteins encoded by SARS-CoV and SARS-CoV-2 antagonize IFN production by retaining phosphorylated IRF3 in the cytoplasm. Our findings have implications in rational design and development of antiviral agents against SARS-CoV-2.

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“…SARS-CoV PLpro has also been reported to also activate TGF-β1 signalling [26] or down-regulate p53 [27]. Similarly for the NSP5 protease, 3CLpro from the feline coronavirus, feline infectious peritonitis virus (FIPV), inhibits type I interferon signalling through cleavage of NEMO [28], while the porcine deltacoronavirus (PDCoV) 3CLpro cleaves DCP1A [29]. SARS-CoV 3CLpro is responsible for virus-induced apoptosis [30].…”

Section: Introductionmentioning

confidence: 99%