Ubiquitin (Ub) and the Ub-like (Ubl) modifier interferon-stimulated gene 15 (ISG15) participate in the host defence of viral infections. Viruses, including the severe acute respiratory syndrome human coronavirus (SARS hCoV), have co-opted Ub–ISG15 conjugation pathways for their own advantage or have evolved effector proteins to counter pro-inflammatory properties of Ub–ISG15-conjugated host proteins. In the present study, we compare substrate specificities of the papain-like protease (PLpro) from the recently emerged Middle East respiratory syndrome (MERS) hCoV to the related protease from SARS, SARS PLpro. Through biochemical assays, we show that, similar to SARS PLpro, MERS PLpro is both a deubiquitinating (DUB) and a deISGylating enzyme. Further analysis of the intrinsic DUB activity of these viral proteases revealed unique differences between the recognition and cleavage specificities of polyUb chains. First, MERS PLpro shows broad linkage specificity for the cleavage of polyUb chains, whereas SARS PLpro prefers to cleave Lys48-linked polyUb chains. Secondly, MERS PLpro cleaves polyUb chains in a ‘mono-distributive’ manner (one Ub at a time) and SARS PLpro prefers to cleave Lys48-linked polyUb chains by sensing a di-Ub moiety as a minimal recognition element using a ‘di-distributive’ cleavage mechanism. The di-distributive cleavage mechanism for SARS PLpro appears to be uncommon among USP (Ub-specific protease)-family DUBs, as related USP family members from humans do not display such a mechanism. We propose that these intrinsic enzymatic differences between SARS and MERS PLpro will help to identify pro-inflammatory substrates of these viral DUBs and can guide in the design of therapeutics to combat infection by coronaviruses.
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Research Article|
May 22 2015
SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme
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Miklós Békés;
Miklós Békés
*Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, U.S.A.
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Wioletta Rut;
Wioletta Rut
†Division of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wyb. Wyspianskiego 27, Wroclaw 50-370, Poland
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Paulina Kasperkiewicz;
Paulina Kasperkiewicz
†Division of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wyb. Wyspianskiego 27, Wroclaw 50-370, Poland
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Monique P.C. Mulder;
Monique P.C. Mulder
‡Division of Cell Biology, Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
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Huib Ovaa;
Huib Ovaa
‡Division of Cell Biology, Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
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Marcin Drag;
Marcin Drag
†Division of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wyb. Wyspianskiego 27, Wroclaw 50-370, Poland
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Christopher D. Lima;
Christopher D. Lima
§Structural Biology Program, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, U.S.A.
║Howard Hughes Medical Institute, 1275 York Ave, New York, NY 10065, U.S.A.
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Tony T. Huang
Tony T. Huang
1
*Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, U.S.A.
1To whom correspondence should be addressed (email tony.huang@nyumc.org).
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Publisher: Portland Press Ltd
Received:
September 16 2014
Revision Received:
March 03 2015
Accepted:
March 13 2015
Accepted Manuscript online:
March 13 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal Compilation © 2015 Biochemical Society
2015
Biochem J (2015) 468 (2): 215–226.
Article history
Received:
September 16 2014
Revision Received:
March 03 2015
Accepted:
March 13 2015
Accepted Manuscript online:
March 13 2015
Citation
Miklós Békés, Wioletta Rut, Paulina Kasperkiewicz, Monique P.C. Mulder, Huib Ovaa, Marcin Drag, Christopher D. Lima, Tony T. Huang; SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme. Biochem J 1 June 2015; 468 (2): 215–226. doi: https://doi.org/10.1042/BJ20141170
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