Demonstrating the importance of porcine reproductive and respiratory syndrome virus papain-like protease 2 deubiquitinating activity in viral replication by structure-guided mutagenesis.

Autor: Bailey-Elkin BA; Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada., Knaap RCM; Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, The Netherlands., De Silva A; Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada., Boekhoud IM; Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, The Netherlands., Mous S; Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, The Netherlands., van Vught N; Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, The Netherlands., Khajehpour M; Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada., van den Born E; MSD Animal Health, Boxmeer, The Netherlands., Kikkert M; Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, The Netherlands., Mark BL; Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Dec 14; Vol. 19 (12), pp. e1011872. Date of Electronic Publication: 2023 Dec 14 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011872
Abstrakt: Deubiquitination of cellular substrates by viral proteases is a mechanism used to interfere with host cellular signaling processes, shared between members of the coronavirus- and arterivirus families. In the case of Arteriviruses, deubiquitinating and polyprotein processing activities are accomplished by the virus-encoded papain-like protease 2 (PLP2). Several studies have implicated the deubiquitinating activity of the porcine reproductive and respiratory syndrome virus (PRRSV) PLP2 in the downregulation of cellular interferon production, however to date, the only arterivirus PLP2 structure described is that of equine arteritis virus (EAV), a distantly related virus. Here we describe the first crystal structure of the PRRSV PLP2 domain both in the presence and absence of its ubiquitin substrate, which reveals unique structural differences in this viral domain compared to PLP2 from EAV. To probe the role of PRRSV PLP2 deubiquitinating activity in host immune evasion, we selectively removed this activity from the domain by mutagenesis and found that the viral domain could no longer downregulate cellular interferon production. Interestingly, unlike EAV, and also unlike the situation for MERS-CoV, we found that recombinant PRRSV carrying PLP2 DUB-specific mutations faces significant selective pressure to revert to wild-type virus in MARC-145 cells, suggesting that the PLP2 DUB activity, which in PRRSV is present as three different versions of viral protein nsp2 expressed during infection, is critically important for PRRSV replication.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Bailey-Elkin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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