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Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity.

ABSTRACT: 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-?B 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, pDCP1A_1-343 and pDCP1A_344-580, 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-?B 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.

SUBMITTER: Zhu X

PROVIDER: S-EPMC7375372 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity.

Zhu Xinyu X Chen Jiyao J Tian Liyuan L Zhou Yanrong Y Xu Shangen S Long Siwen S Wang Dang D Fang Liurong L Xiao Shaobo S

Journal of virology 20200716 15

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 ...[more]

PMID: 32461317

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Project description:Protein acetylation plays an important role during virus infection. Thus, it is not surprising that viruses always evolve elaborate mechanisms to regulate the functions of histone deacetylases (HDACs), the essential transcriptional and epigenetic regulators for deacetylation. Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus, causes severe diarrhea in suckling piglets and has the potential to infect humans. In this study, we found that PDCoV infection inhibited cellular HDAC activity. By screening the expressions of different HDAC subfamilies after PDCoV infection, we unexpectedly found that HDAC2 was cleaved. Ectopic expression of HDAC2 significantly inhibited PDCoV replication, while the reverse effects could be observed after treatment with an HDAC2 inhibitor (CAY10683) or the knockdown of HDAC2 expression by specific siRNA. Furthermore, we demonstrated that PDCoV-encoded nonstructural protein 5 (nsp5), a 3C-like protease, was responsible for HDAC2 cleavage through its protease activity. Detailed analyses showed that PDCoV nsp5 cleaved HDAC2 at glutamine 261 (Q261), and the cleaved fragments (amino acids 1 to 261 and 262 to 488) lost the ability to inhibit PDCoV replication. Interestingly, the Q261 cleavage site is highly conserved in HDAC2 homologs from other mammalian species, and the nsp5s encoded by seven tested mammalian coronaviruses also cleaved HDAC2, suggesting that cleaving HDAC2 may be a common strategy used by different mammalian coronaviruses to antagonize the antiviral role of HDAC2. IMPORTANCE As an emerging porcine enteropathogenic coronavirus that possesses the potential to infect humans, porcine deltacoronavirus (PDCoV) is receiving increasing attention. In this work, we found that PDCoV infection downregulated cellular histone deacetylase (HDAC) activity. Of particular interest, the viral 3C-like protease, encoded by the PDCoV nonstructural protein 5 (nsp5), cleaved HDAC2, and this cleavage could be observed in the context of PDCoV infection. Furthermore, the cleavage of HDAC2 appears to be a common strategy among mammalian coronaviruses, including the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to antagonize the antiviral role of HDAC2. To our knowledge, PDCoV nsp5 is the first identified viral protein that can cleave cellular HDAC2. Results from our study provide new targets to develop drugs combating coronavirus infection.

Project description:Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus. The first outbreak of PDCoV was announced from the United States in 2014, followed by reports in Asia. The nonstructural protein nsp5 is a 3C-like protease of coronavirus, and our previous study showed that PDCoV nsp5 inhibits type I interferon (IFN) production. In this study, we found that PDCoV nsp5 significantly inhibited IFN-stimulated response element (ISRE) promoter activity and transcription of IFN-stimulated genes (ISGs), suggesting that PDCoV nsp5 also suppresses IFN signaling. Detailed analysis showed that nsp5 cleaved signal transducer and activator of transcription 2 (STAT2) but not Janus kinase 1 (JAK1), tyrosine kinase 2 (TYK2), STAT1, and interferon regulatory factor 9 (IRF9), key molecules of the JAK-STAT pathway. STAT2 cleavage was dependent on the protease activity of nsp5. Interestingly, nsp5 cleaved STAT2 at two sites, glutamine 685 (Q685) and Q758, and similar cleavage was observed in PDCoV-infected cells. As expected, cleaved STAT2 impaired the ability to induce ISGs, demonstrating that STAT2 cleavage is an important mechanism utilized by PDCoV nsp5 to antagonize IFN signaling. We also discussed the substrate selection and binding mode of PDCoV nsp5 by homologous modeling of PDCoV nsp5 with the two cleaved peptide substrates. The results of our study demonstrate that PDCoV nsp5 antagonizes type I IFN signaling by cleaving STAT2 and provides structural insights for comprehending the cleavage mechanism of PDCoV nsp5, revealing a potential new function for PDCoV nsp5 in type I IFN signaling.IMPORTANCE The 3C-like protease encoded by nsp5 is a major protease of coronaviruses; thus, it is an attractive target for development of anticoronavirus drugs. Previous studies have revealed that the 3C-like protease of coronaviruses, including PDCoV and porcine epidemic diarrhea virus (PEDV), antagonizes type I IFN production by targeting the NF-κB essential modulator (NEMO). Here, for the first time, we demonstrate that overexpression of PDCoV nsp5 also antagonizes IFN signaling by cleaving STAT2, an essential component of transcription factor complex ISGF3, and that PDCoV infection reduces the levels of STAT2, which may affect the innate immune response.

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Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity.

Publications

Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity.

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