PMID- 31092569
OWN - NLM
STAT- MEDLINE
DCOM- 20200601
LR  - 20200601
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 93
IP  - 15
DP  - 2019 Aug 1
TI  - Porcine Reproductive and Respiratory Syndrome Virus nsp11 Antagonizes Type I 
      Interferon Signaling by Targeting IRF9.
LID - 10.1128/JVI.00623-19 [doi]
LID - e00623-19
AB  - Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus 
      from the Nidovirales order that causes reproductive failure and respiratory 
      disease in pigs and poses a constant threat to the global pig industry. The 
      PRRSV-encoded nonstructural protein 11 (nsp11) is a nidovirus-specific 
      endoribonuclease (NendoU) that is conserved throughout the Arteriviridae and 
      Coronaviridae families. Previously, our research and that of others demonstrated 
      that PRRSV nsp11 inhibits type I interferon (IFN) production through NendoU 
      activity-dependent mechanisms. Here, we found that PRRSV nsp11 also inhibited 
      IFN-stimulated response element (ISRE) promoter activity and subsequent 
      transcription of IFN-stimulated genes (ISGs). Detailed analysis showed that nsp11 
      targeted interferon regulatory factor 9 (IRF9), but not transducer and activator 
      of transcription 1 (STAT1) or STAT2, key molecules in the type I IFN signaling 
      pathway. Furthermore, the nsp11-IRF9 interaction impaired the formation and 
      nuclear translocation of the transcription factor complex IFN-stimulated gene 
      factor 3 (ISGF3) in both nsp11-overexpressed and PRRSV-infected cells. 
      Importantly, nsp11 mutations (H129A, H144A, and K173A) that ablate NendoU 
      activity or its cell cytotoxicity also interacted with IRF9 and retained the 
      ability to block IFN signaling, indicating that the nsp11-IRF9 interaction is 
      independent of NendoU activity or cell cytotoxicity of nsp11. Taking the results 
      together, our study demonstrated that PRRSV nsp11 antagonizes type I IFN 
      signaling by targeting IRF9 via a NendoU activity-independent mechanism, and this 
      report describes a novel strategy evolved by PRRSV to counteract host innate 
      antiviral responses, revealing a potential new function for PRRSV nsp11 in type I 
      IFN signaling.IMPORTANCE The nidovirus-specific endoribonuclease (NendoU) encoded 
      by PRRSV nonstructural protein 11 (nsp11) is a unique NendoU of nidoviruses that 
      infect vertebrates; thus, it is an attractive target for the development of 
      antinidovirus drugs. Previous studies have revealed that the NendoU of 
      nidoviruses, including porcine reproductive and respiratory syndrome virus 
      (PRRSV) and human coronavirus 229E (HCoV-229E), acts as a type I interferon (IFN) 
      antagonist. Here, for the first time, we demonstrated that overexpression of 
      PRRSV nsp11 also inhibits IFN signaling by targeting the C-terminal interferon 
      regulatory factor (IRF) association domain of IRF9. This interaction impaired the 
      ability of IRF9 to form the transcription factor complex IFN-stimulated gene 
      factor 3 (ISGF3) and to act as a signaling protein of IFN signaling. 
      Collectively, our data identify IRF9 as a natural target of PRRSV NendoU and 
      reveal a novel mechanism evolved by an arterivirus to counteract innate immune 
      signaling.
CI  - Copyright (c) 2019 American Society for Microbiology.
FAU - Wang, Dang
AU  - Wang D
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University. Wuhan, Hubei, China.
AD  - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, 
      China.
FAU - Chen, Jiyao
AU  - Chen J
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University. Wuhan, Hubei, China.
AD  - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, 
      China.
FAU - Yu, Chaoliang
AU  - Yu C
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University. Wuhan, Hubei, China.
AD  - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, 
      China.
FAU - Zhu, Xinyu
AU  - Zhu X
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University. Wuhan, Hubei, China.
AD  - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, 
      China.
FAU - Xu, Shangen
AU  - Xu S
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University. Wuhan, Hubei, China.
AD  - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, 
      China.
FAU - Fang, Liurong
AU  - Fang L
AUID- ORCID: 0000-0003-1406-6409
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University. Wuhan, Hubei, China.
AD  - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, 
      China.
FAU - Xiao, Shaobo
AU  - Xiao S
AUID- ORCID: 0000-0003-0023-9188
AD  - State Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University. Wuhan, Hubei, China 
      vet@mail.hzau.edu.cn.
AD  - Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190717
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (IRF9 protein, human)
RN  - 0 (Interferon Type I)
RN  - 0 (Interferon-Stimulated Gene Factor 3, gamma Subunit)
RN  - 0 (Viral Nonstructural Proteins)
RN  - EC 3.1.- (Endoribonucleases)
RN  - EC 3.1.- (nidoviral uridylate-specific endoribonuclease)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Endoribonucleases/*metabolism
MH  - *Host-Pathogen Interactions
MH  - Humans
MH  - *Immune Evasion
MH  - Interferon Type I/*metabolism
MH  - Interferon-Stimulated Gene Factor 3, gamma Subunit/*antagonists & inhibitors
MH  - Porcine respiratory and reproductive syndrome virus/growth & 
      development/*immunology
MH  - *Signal Transduction
MH  - Swine
MH  - Viral Nonstructural Proteins/*metabolism
PMC - PMC6639278
OTO - NOTNLM
OT  - interferon regulatory factor 9
OT  - nidovirus-specific endoribonuclease
OT  - porcine reproductive and respiratory syndrome virus
OT  - type I IFN signaling
EDAT- 2019/05/17 06:00
MHDA- 2020/06/02 06:00
PMCR- 2019/07/17
CRDT- 2019/05/17 06:00
PHST- 2019/04/14 00:00 [received]
PHST- 2019/05/06 00:00 [accepted]
PHST- 2019/05/17 06:00 [pubmed]
PHST- 2020/06/02 06:00 [medline]
PHST- 2019/05/17 06:00 [entrez]
PHST- 2019/07/17 00:00 [pmc-release]
AID - JVI.00623-19 [pii]
AID - 00623-19 [pii]
AID - 10.1128/JVI.00623-19 [doi]
PST - epublish
SO  - J Virol. 2019 Jul 17;93(15):e00623-19. doi: 10.1128/JVI.00623-19. Print 2019 Aug 
      1.