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Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease.
J Gen Virol. 2014 Mar; 95(Pt 3):614-26.JG

Abstract

The emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe pulmonary disease in humans and represents the second example of a highly pathogenic coronavirus (CoV) following severe acute respiratory syndrome coronavirus (SARS-CoV). Genomic studies revealed that two viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), process the polyproteins encoded by the MERS-CoV genomic RNA. We previously reported that SARS-CoV PLpro acts as both deubiquitinase (DUB) and IFN antagonist, but the function of the MERS-CoV PLpro was poorly understood. In this study, we characterized MERS-CoV PLpro, which is a protease and can recognize and process the cleavage sites (CS) of nsp1-2, nsp2-3 and nsp3-4. The LXGG consensus cleavage sites in the N terminus of pp1a/1ab, which is generally essential for CoV PLpro-mediated processing, were also characterized in MERS-CoV. MERS-CoV PLpro, like human SARS-CoV PLpro and NL63-CoV PLP2, is a viral deubiquitinating enzyme. It acts on both K48- and K63-linked ubiquitination and ISG15-linked ISGylation. We confirmed that MERS-CoV PLpro acts as an IFN antagonist through blocking the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3). These findings indicate that MERS-CoV PLpro acts as a viral DUB and suppresses production of IFN-β by an interfering IRF3-mediated signalling pathway, in addition to recognizing and processing the CS at the N terminus of replicase polyprotein to release the non-structural proteins. The characterization of proteolytic processing, DUB and IFN antagonist activities of MERS-CoV PLpro would reveal the interactions between MERS-CoV and its host, and be applicable to develop strategies targeting PLpro for the effective control of MERS-CoV infection.

Authors+Show Affiliations

Division of Infection and Immunity, Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24362959

Citation

Yang, Xingxing, et al. "Proteolytic Processing, Deubiquitinase and Interferon Antagonist Activities of Middle East Respiratory Syndrome Coronavirus Papain-like Protease." The Journal of General Virology, vol. 95, no. Pt 3, 2014, pp. 614-26.
Yang X, Chen X, Bian G, et al. Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease. J Gen Virol. 2014;95(Pt 3):614-26.
Yang, X., Chen, X., Bian, G., Tu, J., Xing, Y., Wang, Y., & Chen, Z. (2014). Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease. The Journal of General Virology, 95(Pt 3), 614-26. https://doi.org/10.1099/vir.0.059014-0
Yang X, et al. Proteolytic Processing, Deubiquitinase and Interferon Antagonist Activities of Middle East Respiratory Syndrome Coronavirus Papain-like Protease. J Gen Virol. 2014;95(Pt 3):614-26. PubMed PMID: 24362959.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease. AU - Yang,Xingxing, AU - Chen,Xiaojuan, AU - Bian,Guangxing, AU - Tu,Jian, AU - Xing,Yaling, AU - Wang,Yayun, AU - Chen,Zhongbin, Y1 - 2013/12/20/ PY - 2013/12/24/entrez PY - 2013/12/24/pubmed PY - 2014/5/3/medline SP - 614 EP - 26 JF - The Journal of general virology JO - J. Gen. Virol. VL - 95 IS - Pt 3 N2 - The emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe pulmonary disease in humans and represents the second example of a highly pathogenic coronavirus (CoV) following severe acute respiratory syndrome coronavirus (SARS-CoV). Genomic studies revealed that two viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), process the polyproteins encoded by the MERS-CoV genomic RNA. We previously reported that SARS-CoV PLpro acts as both deubiquitinase (DUB) and IFN antagonist, but the function of the MERS-CoV PLpro was poorly understood. In this study, we characterized MERS-CoV PLpro, which is a protease and can recognize and process the cleavage sites (CS) of nsp1-2, nsp2-3 and nsp3-4. The LXGG consensus cleavage sites in the N terminus of pp1a/1ab, which is generally essential for CoV PLpro-mediated processing, were also characterized in MERS-CoV. MERS-CoV PLpro, like human SARS-CoV PLpro and NL63-CoV PLP2, is a viral deubiquitinating enzyme. It acts on both K48- and K63-linked ubiquitination and ISG15-linked ISGylation. We confirmed that MERS-CoV PLpro acts as an IFN antagonist through blocking the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3). These findings indicate that MERS-CoV PLpro acts as a viral DUB and suppresses production of IFN-β by an interfering IRF3-mediated signalling pathway, in addition to recognizing and processing the CS at the N terminus of replicase polyprotein to release the non-structural proteins. The characterization of proteolytic processing, DUB and IFN antagonist activities of MERS-CoV PLpro would reveal the interactions between MERS-CoV and its host, and be applicable to develop strategies targeting PLpro for the effective control of MERS-CoV infection. SN - 1465-2099 UR - https://www.unboundmedicine.com/medline/citation/24362959/Proteolytic_processing_deubiquitinase_and_interferon_antagonist_activities_of_Middle_East_respiratory_syndrome_coronavirus_papain_like_protease_ L2 - http://jgv.microbiologyresearch.org/pubmed/content/journal/jgv/10.1099/vir.0.059014-0 DB - PRIME DP - Unbound Medicine ER -