PMID- 38096325
OWN - NLM
STAT- MEDLINE
DCOM- 20231229
LR  - 20240106
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 19
IP  - 12
DP  - 2023 Dec
TI  - Demonstrating the importance of porcine reproductive and respiratory syndrome 
      virus papain-like protease 2 deubiquitinating activity in viral replication by 
      structure-guided mutagenesis.
PG  - e1011872
LID - 10.1371/journal.ppat.1011872 [doi]
LID - e1011872
AB  - 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.
CI  - Copyright: (c) 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.
FAU - Bailey-Elkin, Ben A
AU  - Bailey-Elkin BA
AD  - Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
FAU - Knaap, Robert C M
AU  - Knaap RCM
AD  - Molecular Virology Laboratory, Department of Medical Microbiology, Leiden 
      University Center of Infectious Diseases (LU-CID), Leiden University Medical 
      Center, Leiden, The Netherlands.
FAU - De Silva, Anuradha
AU  - De Silva A
AD  - Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
FAU - Boekhoud, Ilse M
AU  - Boekhoud IM
AD  - Molecular Virology Laboratory, Department of Medical Microbiology, Leiden 
      University Center of Infectious Diseases (LU-CID), Leiden University Medical 
      Center, Leiden, The Netherlands.
FAU - Mous, Sandra
AU  - Mous S
AD  - Molecular Virology Laboratory, Department of Medical Microbiology, Leiden 
      University Center of Infectious Diseases (LU-CID), Leiden University Medical 
      Center, Leiden, The Netherlands.
FAU - van Vught, Niek
AU  - van Vught N
AD  - Molecular Virology Laboratory, Department of Medical Microbiology, Leiden 
      University Center of Infectious Diseases (LU-CID), Leiden University Medical 
      Center, Leiden, The Netherlands.
FAU - Khajehpour, Mazdak
AU  - Khajehpour M
AD  - Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada.
FAU - van den Born, Erwin
AU  - van den Born E
AD  - MSD Animal Health, Boxmeer, The Netherlands.
FAU - Kikkert, Marjolein
AU  - Kikkert M
AD  - Molecular Virology Laboratory, Department of Medical Microbiology, Leiden 
      University Center of Infectious Diseases (LU-CID), Leiden University Medical 
      Center, Leiden, The Netherlands.
FAU - Mark, Brian L
AU  - Mark BL
AUID- ORCID: 0000-0002-7344-1355
AD  - Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
LA  - eng
PT  - Journal Article
DEP - 20231214
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - EC 3.4.22.2 (Papain)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - 9008-11-1 (Interferons)
RN  - 0 (Viral Nonstructural Proteins)
SB  - IM
MH  - Animals
MH  - Horses
MH  - Swine
MH  - Humans
MH  - Papain/chemistry/genetics/metabolism
MH  - *Porcine respiratory and reproductive syndrome virus/genetics/metabolism
MH  - Mutagenesis
MH  - *Equartevirus
MH  - Peptide Hydrolases/genetics
MH  - Virus Replication
MH  - Interferons/genetics
MH  - Viral Nonstructural Proteins/metabolism
PMC - PMC10754444
COIS- The authors have declared that no competing interests exist.
EDAT- 2023/12/14 18:43
MHDA- 2023/12/29 06:43
PMCR- 2023/12/14
CRDT- 2023/12/14 14:08
PHST- 2023/02/07 00:00 [received]
PHST- 2023/11/28 00:00 [accepted]
PHST- 2023/12/28 00:00 [revised]
PHST- 2023/12/29 06:43 [medline]
PHST- 2023/12/14 18:43 [pubmed]
PHST- 2023/12/14 14:08 [entrez]
PHST- 2023/12/14 00:00 [pmc-release]
AID - PPATHOGENS-D-23-00236 [pii]
AID - 10.1371/journal.ppat.1011872 [doi]
PST - epublish
SO  - PLoS Pathog. 2023 Dec 14;19(12):e1011872. doi: 10.1371/journal.ppat.1011872. 
      eCollection 2023 Dec.