Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 4 Cleaves Porcine DCP1a To Attenuate Its Antiviral Activity

Tao, Ran; Fang, Liurong; Bai, Dongcheng; Ke, Wenting; Zhou, Yanrong; Wang, Dan; Xiao, Shaobo

doi:10.4049/jimmunol.1701773

Cited by 23 publications

(16 citation statements)

References 59 publications

(71 reference statements)

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“…Our previous study showed that porcine reproductive and respiratory syndrome virus (PRRSV) nsp4 cleaves pDCP1A but not the human or monkey DCP1A homolog (68). Contrary to the species-specific cleavage mediated by PRRSV nsp4 at residue E238 of pDCP1A, residue Q343 and the peptide nearby are quite conserved among different mammalian species of DCP1A, providing a natural substrate for CoV nsp5.…”

Section: Discussionmentioning

confidence: 97%

Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity

Zhu

Chen

Tian

et al. 2020

J Virol

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Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus. The nonstructural protein nsp5, also called 3C-like protease, is responsible for processing viral polyprotein precursors in coronavirus (CoV) replication. Previous studies have shown that PDCoV nsp5 cleaves the NF-κB essential modulator and the signal transducer and activator of transcription 2 to disrupt interferon (IFN) production and signaling, respectively. Whether PDCoV nsp5 also cleaves IFN-stimulated genes (ISGs), IFN-induced antiviral effector molecules, remains unclear. In this study, we screened 14 classical ISGs and found that PDCoV nsp5 cleaved the porcine mRNA-decapping enzyme 1a (pDCP1A) through its protease activity. Similar cleavage of endogenous pDCP1A was also observed in PDCoV-infected cells. PDCoV nsp5 cleaved pDCP1A at glutamine 343 (Q343), and the cleaved pDCP1A fragments, pDCP1A1–343 and pDCP1A344–580, were unable to inhibit PDCoV infection. Mutant pDCP1A-Q343A, which resists nsp5-mediated cleavage, exhibited a stronger ability to inhibit PDCoV infection than wild-type pDCP1A. Interestingly, the Q343 cleavage site is highly conserved in DCP1A homologs from other mammalian species. Further analyses demonstrated that nsp5 encoded by seven tested CoVs that can infect human or pig also cleaved pDCP1A and human DCP1A, suggesting that DCP1A may be the common target for cleavage by nsp5 of mammalian CoVs. IMPORTANCE Interferon (IFN)-stimulated gene (ISG) induction through IFN signaling is important to create an antiviral state and usually directly inhibits virus infection. The present study first demonstrated that PDCoV nsp5 can cleave mRNA-decapping enzyme 1a (DCP1A) to attenuate its antiviral activity. Furthermore, cleaving DCP1A is a common characteristic of nsp5 proteins from different coronaviruses (CoVs), which represents a common immune evasion mechanism of CoVs. Previous evidence showed that CoV nsp5 cleaves the NF-κB essential modulator and signal transducer and activator of transcription 2. Taken together, CoV nsp5 is a potent IFN antagonist because it can simultaneously target different aspects of the host IFN system, including IFN production and signaling and effector molecules.

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Section: Discussionmentioning

confidence: 97%

Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity

Zhu

Chen

Tian

et al. 2020

J Virol

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“…PRRSV Nsp4 has inhibitory effects on IFN-β, NF-κB, and IRF3, thus suppressing the host’s innate immune mechanism ( Chen et al, 2014 ). Moreover, Nsp4 can proteolytically cleave the host’s antiviral genes to antagonize antiviral activity, such as NF-κB essential modulator (NEMO), zinc finger antiviral protein (ZAP), mRNA-decapping enzyme 1a (DCP1a), and virus-induced signaling adaptor (VISA; Huang et al, 2016 ; Tao et al, 2018 ; Chen et al, 2019 ; Zhao et al, 2020 ). Considering the proteolytic enzyme activity of Nsp4, the decrease in PKR protein is possibly caused by the cleavage of Nsp4.…”

Section: Discussionmentioning

confidence: 99%

Induction of UPR Promotes Interferon Response to Inhibit PRRSV Replication via PKR and NF-κB Pathway

et al. 2021

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Porcine reproductive and respiratory syndrome virus (PRRSV) was previously shown to induce a certain level of cellular stress during viral replication. Unfolded protein response (UPR) is a cellular stress response responsible for coping with stress and cellular survival. However, the pathway leading to the induction of UPR that may influence PRRSV replication is still unknown. Here, we found that PRRSV infection induced UPR prior to interferon response. Induction of UPR significantly enhanced the expression of interferon and interferon-related genes, thus leading to the suppression of PRRSV infection. Next, we explored the underlying mechanisms of UPR-induced antiviral response. We found that induction of UPR promoted the expression of protein kinase R (PKR), and PKR was highly correlated with the reduction of PRRSV replication. Furthermore, tunicamycin stimulation and PKR overexpression activated NF-κB and interferon response at the early stage of PRRSV infection, thus reinforcing the expression of type I interferons and proinflammatory cytokines and leading to inhibition of PRRSV. In addition, PRRSV nsp4 was shown to reduce the expression of PKR. These findings might have implications for our understandings of the host’s immune mechanism against PRRSV and a new strategy of PRRSV to evade the host antiviral immunity.

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“…However, hCH25H showed greater antiviral activity against PRRSV, compared with pCH25H. Recently, our group showed that the PRRSV 3C-like proteinase nsp4 cleaves porcine mRNA-decapping enzyme 1a (pDCP1a), an ISG (60). Human and monkey DCP1a were not be cleaved by PRRSV nsp4, however, because the cleavage site at Glu237 in pDCP1a is substituted with Asp in the human and monkey orthologues.…”

Section: Discussionmentioning

confidence: 99%

Porcine Reproductive and Respiratory Syndrome Virus E Protein Degrades Porcine Cholesterol 25-Hydroxylase via the Ubiquitin-Proteasome Pathway

Fang

Tao

et al. 2019

J Virol

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Porcine reproductive and respiratory syndrome is one of the most important infectious diseases affecting the global pig industry. Previous studies from our group and other groups showed that cholesterol 25-hydroxylase (CH25H), a multitransmembrane endoplasmic reticulum-associated enzyme, catalyzes the production of 25-hydroxycholesterol (25HC) and inhibits porcine reproductive and respiratory syndrome virus (PRRSV) replication. However, PRRSV infection also actively decreases porcine CH25H (pCH25H) expression, through unidentified mechanisms. In this study, we found that the ubiquitin-proteasome pathway plays a major role in pCH25H degradation during PRRSV infection and that the PRRSV-encoded envelope (E) protein interacts with pCH25H. PRRSV E protein degraded pCH25H via ubiquitination, and the ubiquitination site was at pCH25H Lys28. Interestingly, PRRSV E protein appeared to specifically degrade pCH25H but not human CH25H, likely because of a Lys28Arg substitution in the human orthologue. As expected, ubiquitin-mediated degradation by E protein attenuated the antiviral effect of pCH25H by downregulating 25HC production. In addition, we found that knockdown of pCH25H decreased E protein-induced inflammatory cytokine expression and that pCH25H overexpression had the opposite effect. These findings suggested that regulation of pCH25H expression was associated with E protein-induced inflammatory responses. Taken together, our results and those of previous studies of the anti-PRRSV effects of CH25H highlight the complex interplay between PRRSV and pCH25H. IMPORTANCE CH25H has received significant attention due to its broad antiviral activity, which it mediates by catalyzing the production of 25HC. Most studies have focused on the antiviral mechanisms of CH25H; however, whether viruses also actively regulate CH25H expression has not yet been reported. Previous studies demonstrated that pCH25H inhibits PRRSV replication not only via production of 25HC but also by ubiquitination and degradation of viral nonstructural protein 1α. In this study, we expanded on previous work and found that PRRSV actively degrades pCH25H through the ubiquitin-proteasome pathway. PRRSV E protein, a viral structural protein, is involved in this process. This study reveals a novel mechanism of interaction between virus and host during PRRSV infection.

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Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 4 Cleaves Porcine DCP1a To Attenuate Its Antiviral Activity

Cited by 23 publications

References 59 publications

Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity

Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity

Induction of UPR Promotes Interferon Response to Inhibit PRRSV Replication via PKR and NF-κB Pathway

Porcine Reproductive and Respiratory Syndrome Virus E Protein Degrades Porcine Cholesterol 25-Hydroxylase via the Ubiquitin-Proteasome Pathway

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