PMID- 34287043
OWN - NLM
STAT- MEDLINE
DCOM- 20210922
LR  - 20220310
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 95
IP  - 19
DP  - 2021 Sep 9
TI  - EGR1 Suppresses Porcine Epidemic Diarrhea Virus Replication by Regulating IRAV To 
      Degrade Viral Nucleocapsid Protein.
PG  - e0064521
LID - 10.1128/JVI.00645-21 [doi]
LID - e00645-21
AB  - Porcine epidemic diarrhea virus (PEDV) is a globally distributed alphacoronavirus 
      that has reemerged lately, resulting in large economic losses. During viral 
      infection, type I interferon (IFN-I) plays a vital role in the antiviral innate 
      immunity. However, PEDV has evolved strategies to limit IFN-I production. To 
      suppress virus replication, the host must activate IFN-stimulated genes and some 
      host restriction factors to circumvent viral replication. This study observed 
      that PEDV infection induced early growth response gene 1 (EGR1) expression in 
      PEDV-permissive cells. EGR1 overexpression remarkably suppressed PEDV 
      replication. In contrast, depletion of EGR1 led to a significant increase in 
      viral replication. EGR1 suppressed PEDV replication by directly binding to the 
      IFN-regulated antiviral (IRAV) promoter and upregulating IRAV expression. A 
      detailed analysis revealed that IRAV interacts and colocalizes with the PEDV 
      nucleocapsid (N) protein, inducing N protein degradation via the E3 ubiquitin 
      ligase MARCH8 to catalyze N protein ubiquitination. Knockdown of endogenous 
      MARCH8 significantly reversed IRAV-mediated N protein degradation. The collective 
      findings demonstrate a new mechanism of EGR1-mediated viral restriction, in which 
      EGR1 upregulates the expression of IRAV to degrade PEDV N protein through MARCH8. 
      IMPORTANCE PEDV is a highly contagious enteric coronavirus that has rapidly 
      emerged worldwide and has caused severe economic losses. No currently available 
      drugs or vaccines can effectively control PEDV. PEDV has evolved many strategies 
      to limit IFN-I production. We identified EGR1 as a novel host restriction factor 
      and demonstrated that EGR1 suppresses PEDV replication by directly binding to the 
      IRAV promoter and upregulating the expression of IRAV, which interacts with and 
      degrades the PEDV N protein via the E3 ubiquitin ligase MARCH8 to catalyze 
      nucleocapsid protein ubiquitination, which adds another layer of complexity to 
      the innate antiviral immunity of this newly identified restriction factor. A 
      better understanding of the innate immune response to PEDV infection will aid the 
      development of novel therapeutic targets and more effective vaccines against 
      virus infection.
FAU - Wang, Hua
AU  - Wang H
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
FAU - Kong, Ning
AU  - Kong N
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
AD  - Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal 
      Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's 
      Republic of China.
FAU - Jiao, Yajuan
AU  - Jiao Y
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
FAU - Dong, Sujie
AU  - Dong S
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
FAU - Sun, Dage
AU  - Sun D
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
FAU - Chen, Xiaoyong
AU  - Chen X
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
FAU - Zheng, Hao
AU  - Zheng H
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
AD  - Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal 
      Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's 
      Republic of China.
FAU - Tong, Wu
AU  - Tong W
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
AD  - Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal 
      Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's 
      Republic of China.
FAU - Yu, Hai
AU  - Yu H
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
AD  - Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal 
      Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's 
      Republic of China.
FAU - Yu, Lingxue
AU  - Yu L
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
AD  - Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal 
      Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's 
      Republic of China.
FAU - Zhang, Wen
AU  - Zhang W
AD  - School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
FAU - Tong, Guangzhi
AU  - Tong G
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
AD  - Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal 
      Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's 
      Republic of China.
FAU - Shan, Tongling
AU  - Shan T
AUID- ORCID: 0000-0002-5329-6349
AD  - Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 
      Shanghai, People's Republic of China.
AD  - Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal 
      Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's 
      Republic of China.
LA  - eng
GR  - 2016YFD0500103/National Key Research and Development Programs of China/
GR  - 19ZR1469100/Natural Science Foundation of Shanghai (Shanghai Natural Science 
      Foundation)/
GR  - 31872478/National Natural Science Foundation of China (NSFC)/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210909
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antiviral Agents)
RN  - 0 (EGR1 protein, human)
RN  - 0 (Early Growth Response Protein 1)
RN  - 0 (Interferon Type I)
RN  - 0 (Nucleocapsid Proteins)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (SHFL protein, human)
RN  - EC 2.3.2.27 (MARCHF8 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/metabolism
MH  - Chlorocebus aethiops
MH  - Coronavirus Infections
MH  - Early Growth Response Protein 1/*metabolism/*pharmacology
MH  - HEK293 Cells
MH  - Host-Pathogen Interactions
MH  - Humans
MH  - Immunity, Innate
MH  - Interferon Type I/metabolism
MH  - Nucleocapsid/metabolism
MH  - Nucleocapsid Proteins/*metabolism
MH  - Porcine epidemic diarrhea virus/*drug effects/genetics
MH  - RNA-Binding Proteins/*metabolism
MH  - Swine
MH  - Swine Diseases/virology
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
MH  - Vero Cells
MH  - Virus Replication/*drug effects
PMC - PMC8428380
OTO - NOTNLM
OT  - EGR1
OT  - IRAV
OT  - PEDV
OT  - antiviral response
OT  - nucleocapsid protein
OT  - viral replication
EDAT- 2021/07/22 06:00
MHDA- 2021/09/23 06:00
PMCR- 2022/03/09
CRDT- 2021/07/21 12:34
PHST- 2021/07/22 06:00 [pubmed]
PHST- 2021/09/23 06:00 [medline]
PHST- 2021/07/21 12:34 [entrez]
PHST- 2022/03/09 00:00 [pmc-release]
AID - 00645-21 [pii]
AID - 10.1128/JVI.00645-21 [doi]
PST - ppublish
SO  - J Virol. 2021 Sep 9;95(19):e0064521. doi: 10.1128/JVI.00645-21. Epub 2021 Sep 9.