PMID- 34911669
OWN - NLM
STAT- MEDLINE
DCOM- 20220310
LR  - 20220311
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 49
DP  - 2022 Feb
TI  - Porcine reproductive and respiratory syndrome virus nsp4 positively regulates 
      cellular cholesterol to inhibit type I interferon production.
PG  - 102207
LID - S2213-2317(21)00367-0 [pii]
LID - 10.1016/j.redox.2021.102207 [doi]
LID - 102207
AB  - Cellular cholesterol plays an important role in the life cycles of enveloped 
      viruses. Previous studies by our group and other groups have demonstrated that 
      the depletion of cellular cholesterol by methyl-beta-cyclodextrin (MbetaCD) reduces the 
      proliferation of porcine reproductive and respiratory syndrome virus (PRRSV), a 
      porcine Arterivirus that has been devastating the swine industry worldwide for 
      over two decades. However, how PRRSV infection regulates cholesterol synthesis is 
      not fully understood. In this study, we showed that PRRSV infection upregulated 
      the activity of protein phosphatase 2 (PP2A), which subsequently activated 
      3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme 
      in the cholesterol synthesis pathway, to increase the levels of cellular 
      cholesterol. By screening the PRRSV-encoded proteins, we showed that nsp4 
      dominated the upregulation of cellular cholesterol, independently of the 3C-like 
      protease activity of nsp4. A mutation analysis showed that domain I (amino acids 
      1-80) of PRRSV nsp4 interacted with PR65 alpha (PR65alpha), the structural subunit, 
      and PP2Ac, the catalytic subunit, of PP2A. Importantly, domain I of nsp4 
      inhibited Sendai virus-induced interferon beta production, and this inhibitory 
      effect was eliminated by Lovastatin, an HMGCR inhibitor, indicating that the 
      upregulation of cellular cholesterol by nsp4 is a strategy used by PRRSV to 
      suppress the antiviral innate immunity of its host. Collectively, we here 
      demonstrated the mechanism by which PRRSV regulates cellular cholesterol 
      synthesis and reported a novel strategy by which PRRSV evades its host's 
      antiviral innate immune response.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Ke, Wenting
AU  - Ke W
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key 
      Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative 
      Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
FAU - Zhou, Yanrong
AU  - Zhou Y
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key 
      Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative 
      Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
FAU - Lai, Yinan
AU  - Lai Y
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key 
      Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative 
      Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
FAU - Long, Siwen
AU  - Long S
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key 
      Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative 
      Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
FAU - Fang, Liurong
AU  - Fang L
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key 
      Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative 
      Innovation Center for Sustainable Pig Production, Wuhan, 430070, China. 
      Electronic address: fanglr@mail.hzau.edu.cn.
FAU - Xiao, Shaobo
AU  - Xiao S
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key 
      Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative 
      Innovation Center for Sustainable Pig Production, Wuhan, 430070, China. 
      Electronic address: vet@mail.hzau.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211208
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Interferon Type I)
RN  - 0 (Viral Nonstructural Proteins)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cholesterol
MH  - *Interferon Type I/metabolism
MH  - *Porcine respiratory and reproductive syndrome virus/metabolism
MH  - Swine
MH  - Viral Nonstructural Proteins/genetics/metabolism
PMC - PMC8758914
OTO - NOTNLM
OT  - AMPK
OT  - Cholesterol
OT  - HMGCR
OT  - Interferon
OT  - PP2A
OT  - PRRSV
COIS- All the authors declare that there are no conflicts of interest.
EDAT- 2021/12/17 06:00
MHDA- 2022/03/11 06:00
PMCR- 2021/12/08
CRDT- 2021/12/16 05:40
PHST- 2021/11/03 00:00 [received]
PHST- 2021/11/26 00:00 [revised]
PHST- 2021/12/07 00:00 [accepted]
PHST- 2021/12/17 06:00 [pubmed]
PHST- 2022/03/11 06:00 [medline]
PHST- 2021/12/16 05:40 [entrez]
PHST- 2021/12/08 00:00 [pmc-release]
AID - S2213-2317(21)00367-0 [pii]
AID - 102207 [pii]
AID - 10.1016/j.redox.2021.102207 [doi]
PST - ppublish
SO  - Redox Biol. 2022 Feb;49:102207. doi: 10.1016/j.redox.2021.102207. Epub 2021 Dec 
      8.