PMID- 35858300
OWN - NLM
STAT- MEDLINE
DCOM- 20220722
LR  - 20230112
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 29
DP  - 2022 Jul 19
TI  - Viral evasion of PKR restriction by reprogramming cellular stress granules.
PG  - e2201169119
LID - 10.1073/pnas.2201169119 [doi]
LID - e2201169119
AB  - Protein kinase R (PKR) is a critical host restriction factor against invading 
      viral pathogens. However, this molecule is inactivated in the cells infected with 
      porcine reproductive and respiratory syndrome virus (PRRSV), an economically 
      devastating pathogen to the world swine industry. Here, we report that this event 
      is to suppress cellular inflammation and is mediated by the viral replicase 
      protein nsp1beta. We show that nsp1beta is a stress-responsive protein, enters 
      virus-induced stress granules (SGs) during infection, and repurposes SGs into a 
      proviral platform, where it co-opts the SG core component G3BP1 to interact with 
      PKR in a regulated manner. RNA interference silencing of G3BP1 or mutation of 
      specific nsp1beta residues (VS19GG) can abolish the antagonization of PKR 
      activation. The viral mutant carrying the corresponding mutations induces 
      elevated level of PKR phosphorylation and pronounced production of inflammatory 
      cytokines (e.g., tumor necrosis factor-alpha, interleukin [IL]-6, and IL-8), whereas 
      small-interfering RNA knockdown of PKR or treatment with C16, a PKR inhibitor, 
      blocks this effect. Thus, PRRSV has evolved a unique strategy to evade PKR 
      restriction to suppress host inflammatory responses.
FAU - Gao, Peng
AU  - Gao P
AUID- ORCID: 0000-0002-8981-4988
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Liu, Yuanyuan
AU  - Liu Y
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Wang, Hua
AU  - Wang H
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Chai, Yue
AU  - Chai Y
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Weng, Wenlian
AU  - Weng W
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Zhang, Yongning
AU  - Zhang Y
AUID- ORCID: 0000-0002-0134-2761
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Zhou, Lei
AU  - Zhou L
AUID- ORCID: 0000-0002-8837-3965
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Ge, Xinna
AU  - Ge X
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Guo, Xin
AU  - Guo X
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Han, Jun
AU  - Han J
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
FAU - Yang, Hanchun
AU  - Yang H
AUID- ORCID: 0000-0003-3359-3925
AD  - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural 
      Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 
      100193, People's Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220711
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antiviral Restriction Factors)
RN  - 0 (Poly-ADP-Ribose Binding Proteins)
RN  - 0 (RNA Recognition Motif Proteins)
RN  - 0 (Viral Nonstructural Proteins)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.6.4.- (DNA Helicases)
RN  - EC 3.6.4.13 (RNA Helicases)
SB  - IM
MH  - Animals
MH  - *Antiviral Restriction Factors/metabolism
MH  - *DNA Helicases/metabolism
MH  - *Immune Evasion
MH  - *Poly-ADP-Ribose Binding Proteins/metabolism
MH  - *Porcine respiratory and reproductive syndrome virus/genetics/metabolism
MH  - *RNA Helicases/metabolism
MH  - *RNA Recognition Motif Proteins/metabolism
MH  - *Stress Granules/virology
MH  - Swine
MH  - *Viral Nonstructural Proteins/metabolism
MH  - Virus Replication
MH  - *eIF-2 Kinase/metabolism
PMC - PMC9303852
OTO - NOTNLM
OT  - PKR
OT  - PRRSV
OT  - inflammation
OT  - nsp1beta
OT  - stress granules
COIS- The authors declare no competing interest.
EDAT- 2022/07/21 06:00
MHDA- 2022/07/23 06:00
PMCR- 2023/01/11
CRDT- 2022/07/20 17:02
PHST- 2022/07/20 17:02 [entrez]
PHST- 2022/07/21 06:00 [pubmed]
PHST- 2022/07/23 06:00 [medline]
PHST- 2023/01/11 00:00 [pmc-release]
AID - 202201169 [pii]
AID - 10.1073/pnas.2201169119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Jul 19;119(29):e2201169119. doi: 
      10.1073/pnas.2201169119. Epub 2022 Jul 11.