PMID- 27997564
OWN - NLM
STAT- MEDLINE
DCOM- 20170630
LR  - 20191210
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 12
DP  - 2016
TI  - Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus 
      Suppresses Both MAVS and RIG-I Expression as One of the Mechanisms to Antagonize 
      Type I Interferon Production.
PG  - e0168314
LID - 10.1371/journal.pone.0168314 [doi]
LID - e0168314
AB  - Type I interferons (IFN-alpha/beta) play a key role in antiviral defense, and porcine 
      reproductive and respiratory syndrome virus (PRRSV) is known to down-regulate the 
      IFN response in virus-infected cells and pigs. In this study, we showed that the 
      overexpression of nsp11 of PRRSV induced a strong suppression of IFN production. 
      Nsp11 suppressed both IRF3 and NF-kappaB activities when stimulated with a dsRNA 
      analogue and TNF-alpha, respectively. This suppression was RLR dependent, since the 
      transcripts and proteins of MAVS and RIG-I, two critical factors in RLR-mediated 
      pathway, were both found to be reduced in the presence of overexpressed nsp11. 
      Since nsp11 is an endoribonuclease (EndoU), the structure function relationship 
      was examined using a series of nsp11 EndoU mutant plasmids. The mutants that 
      impaired the EndoU activity failed to suppress IFN and led to the normal 
      expression of MAVS. Seven single amino acid substitutions (4 in subdomain A and 3 
      in subdomain B) plus one insertion (frame-shift in nsp11) were then introduced 
      into PRRSV infectious cDNA clones to generate nsp11 mutant viruses. 
      Unfortunately, all EndoU knock-out nsp11 mutant viruses appeared 
      replication-defective and no progenies were produced. Three mutations in EndoU 
      subdomain A expressed the N and nsp2/3 proteins but their infectivity diminished 
      after 2 passages. Taken together, our data show that PRRSV nsp11 endoribonuclease 
      activity is critical for both viral replication and IFN antagonism. More 
      importantly, the endoribonuclease activity of nsp11 demonstrates the substrate 
      specificity towards MAVS and RIG-I (transcripts and proteins) over p65 and IRF3 
      in the context of gene transfection and overexpression. This is likely a 
      mechanism of nsp11 suppression of type I IFN production.
FAU - Sun, Yan
AU  - Sun Y
AD  - Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, 
      Illinois, United States of America.
FAU - Ke, Hanzhong
AU  - Ke H
AD  - Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, 
      Illinois, United States of America.
FAU - Han, Mingyuan
AU  - Han M
AD  - Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, 
      Illinois, United States of America.
FAU - Chen, Ning
AU  - Chen N
AD  - Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, 
      Illinois, United States of America.
FAU - Fang, Weihuan
AU  - Fang W
AD  - Institute of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, 
      China.
FAU - Yoo, Dongwan
AU  - Yoo D
AD  - Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, 
      Illinois, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20161220
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Interferon Type I)
RN  - 0 (Viral Nonstructural Proteins)
RN  - EC 3.1.- (Endonucleases)
RN  - EC 3.6.4.13 (DEAD Box Protein 58)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*biosynthesis/genetics
MH  - Amino Acid Substitution
MH  - Animals
MH  - Cell Line
MH  - Chlorocebus aethiops
MH  - Cricetinae
MH  - DEAD Box Protein 58/*biosynthesis/genetics
MH  - Endonucleases/genetics/*metabolism
MH  - *Gene Expression Regulation
MH  - Interferon Type I/*biosynthesis/genetics
MH  - Mutation, Missense
MH  - Porcine respiratory and reproductive syndrome virus/*physiology
MH  - Swine
MH  - Viral Nonstructural Proteins/genetics/*metabolism
MH  - Virus Replication/*physiology
PMC - PMC5172586
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/12/21 06:00
MHDA- 2017/07/01 06:00
PMCR- 2016/12/20
CRDT- 2016/12/21 06:00
PHST- 2016/02/16 00:00 [received]
PHST- 2016/11/29 00:00 [accepted]
PHST- 2016/12/21 06:00 [entrez]
PHST- 2016/12/21 06:00 [pubmed]
PHST- 2017/07/01 06:00 [medline]
PHST- 2016/12/20 00:00 [pmc-release]
AID - PONE-D-16-06703 [pii]
AID - 10.1371/journal.pone.0168314 [doi]
PST - epublish
SO  - PLoS One. 2016 Dec 20;11(12):e0168314. doi: 10.1371/journal.pone.0168314. 
      eCollection 2016.