PMID- 38376196
OWN - NLM
STAT- MEDLINE
DCOM- 20240320
LR  - 20240321
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 98
IP  - 3
DP  - 2024 Mar 19
TI  - Ubiquitin-specific proteinase 1 stabilizes PRRSV nonstructural protein Nsp1beta to 
      promote viral replication by regulating K48 ubiquitination.
PG  - e0168623
LID - 10.1128/jvi.01686-23 [doi]
LID - e01686-23
AB  - The porcine reproductive and respiratory syndrome virus (PRRSV) can lead to 
      severe reproductive problems in sows, pneumonia in weaned piglets, and increased 
      mortality, significantly negatively impacting the economy. Post-translational 
      changes are essential for the host-dependent replication and long-term infection 
      of PRRSV. Uncertainty surrounds the function of the ubiquitin network in PRRSV 
      infection. Here, we screened 10 deubiquitinating enzyme inhibitors and found that 
      the ubiquitin-specific proteinase 1 (USP1) inhibitor ML323 significantly 
      inhibited PRRSV replication in vitro. Importantly, we found that USP1 interacts 
      with nonstructural protein 1beta (Nsp1beta) and deubiquitinates its K48 to increase 
      protein stability, thereby improving PRRSV replication and viral titer. Among 
      them, lysine at position 45 is essential for Nsp1beta protein stability. In 
      addition, deficiency of USP1 significantly reduced viral replication. Moreover, 
      ML323 loses antagonism to PRRSV rSD16-K45R. This study reveals the mechanism by 
      which PRRSV recruits the host factor USP1 to promote viral replication, providing 
      a new target for PRRSV defense.IMPORTANCEDeubiquitinating enzymes are critical 
      factors in regulating host innate immunity. The porcine reproductive and 
      respiratory syndrome virus (PRRSV) nonstructural protein 1beta (Nsp1beta) is essential 
      for producing viral subgenomic mRNA and controlling the host immune system. The 
      host inhibits PRRSV proliferation by ubiquitinating Nsp1beta, and conversely, PRRSV 
      recruits the host protein ubiquitin-specific proteinase 1 (USP1) to remove this 
      restriction. Our results demonstrate the binding of USP1 to Nsp1beta, revealing a 
      balance of antagonism between PRRSV and the host. Our research identifies a 
      brand-new PRRSV escape mechanism from the immune response.
FAU - Zhai, Yunyun
AU  - Zhai Y
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Du, Yongkun
AU  - Du Y
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Yuan, Hang
AU  - Yuan H
AD  - Zhengzhou Shengda University of Economic Business & Management, Zhengzhou, China.
FAU - Fan, Shuai
AU  - Fan S
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Chen, Xing
AU  - Chen X
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Wang, Jiang
AU  - Wang J
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - He, Wenrui
AU  - He W
AUID- ORCID: 0000-0002-4955-3357
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Han, Shichong
AU  - Han S
AUID- ORCID: 0000-0002-1670-8607
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Zhang, Yuhang
AU  - Zhang Y
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Hu, Man
AU  - Hu M
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
FAU - Zhang, Gaiping
AU  - Zhang G
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
AD  - Peking University, Beijing, China.
AD  - Longhu Laboratory, Zhengzhou, China.
FAU - Kong, Zhengjie
AU  - Kong Z
AUID- ORCID: 0000-0002-4937-2898
AD  - Peking University, Beijing, China.
FAU - Wan, Bo
AU  - Wan B
AUID- ORCID: 0000-0001-7900-2831
AD  - College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, 
      China.
AD  - International Joint Research Center for National Animal Immunology, Zhengzhou, 
      Henan, China.
LA  - eng
GR  - 31490601/MOST | National Natural Science Foundation of China (NSFC)/
GR  - 32272987/MOST | National Natural Science Foundation of China (NSFC)/
PT  - Journal Article
DEP - 20240220
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - 0 (Viral Nonstructural Proteins)
SB  - IM
MH  - Animals
MH  - Female
MH  - Endopeptidases/genetics
MH  - Peptide Hydrolases/metabolism
MH  - *Porcine Reproductive and Respiratory Syndrome/metabolism/virology
MH  - *Porcine respiratory and reproductive syndrome virus/metabolism
MH  - Swine
MH  - Viral Nonstructural Proteins/genetics/metabolism
MH  - Virus Replication
PMC - PMC10949481
OTO - NOTNLM
OT  - Nsp1beta
OT  - PRRSV
OT  - USP1
OT  - deubiquitination
OT  - immune escape
COIS- The authors declare no conflict of interest.
EDAT- 2024/02/20 12:51
MHDA- 2024/03/20 06:45
PMCR- 2024/02/20
CRDT- 2024/02/20 09:05
PHST- 2024/03/20 06:45 [medline]
PHST- 2024/02/20 12:51 [pubmed]
PHST- 2024/02/20 09:05 [entrez]
PHST- 2024/02/20 00:00 [pmc-release]
AID - 01686-23 [pii]
AID - jvi.01686-23 [pii]
AID - 10.1128/jvi.01686-23 [doi]
PST - ppublish
SO  - J Virol. 2024 Mar 19;98(3):e0168623. doi: 10.1128/jvi.01686-23. Epub 2024 Feb 20.