PMID- 38436247
OWN - NLM
STAT- MEDLINE
DCOM- 20240417
LR  - 20240502
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 98
IP  - 4
DP  - 2024 Apr 16
TI  - GTPase activity of porcine Mx1 plays a dominant role in inhibiting the N-Nsp9 
      interaction and thus inhibiting PRRSV replication.
PG  - e0184423
LID - 10.1128/jvi.01844-23 [doi]
LID - e01844-23
AB  - Porcine Mx1 is a type of interferon-induced GTPase that inhibits the replication 
      of certain RNA viruses. However, the antiviral effects and the underlying 
      mechanism of porcine Mx1 for porcine reproductive and respiratory syndrome virus 
      (PRRSV) remain unknown. In this study, we demonstrated that porcine Mx1 could 
      significantly inhibit PRRSV replication in MARC-145 cells. By Mx1 segment 
      analysis, it was indicated that the GTPase domain (68-341aa) was the functional 
      area to inhibit PRRSV replication and that Mx1 interacted with the PRRSV-N 
      protein through the GTPase domain (68-341aa) in the cytoplasm. Amino acid 
      residues K295 and K299 in the G domain of Mx1 were the key sites for Mx1-N 
      interaction while mutant proteins Mx1(K295A) and Mx1(K299A) still partially 
      inhibited PRRSV replication. Furthermore, we found that the GTPase activity of 
      Mx1 was dominant for Mx1 to inhibit PRRSV replication but was not essential for 
      Mx1-N interaction. Finally, mechanistic studies demonstrated that the GTPase 
      activity of Mx1 played a dominant role in inhibiting the N-Nsp9 interaction and 
      that the interaction between Mx1 and N partially inhibited the N-Nsp9 
      interaction. We propose that the complete anti-PRRSV mechanism of porcine Mx1 
      contains a two-step process: Mx1 binds to the PRRSV-N protein and subsequently 
      disrupts the N-Nsp9 interaction by a process requiring the GTPase activity of 
      Mx1. Taken together, the results of our experiments describe for the first time a 
      novel mechanism by which porcine Mx1 evolves to inhibit PRRSV replication. 
      IMPORTANCE: Mx1 protein is a key mediator of the interferon-induced antiviral 
      response against a wide range of viruses. How porcine Mx1 affects the replication 
      of porcine reproductive and respiratory syndrome virus (PRRSV) and its biological 
      function has not been studied. Here, we show that Mx1 protein inhibits PRRSV 
      replication by interfering with N-Nsp9 interaction. Furthermore, the GTPase 
      activity of porcine Mx1 plays a dominant role and the Mx1-N interaction plays an 
      assistant role in this interference process. This study uncovers a novel 
      mechanism evolved by porcine Mx1 to exert anti-PRRSV activities.
FAU - Hu, Yue
AU  - Hu Y
AUID- ORCID: 0000-0002-8290-9845
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Wu, Xiangju
AU  - Wu X
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Tian, Yunfei
AU  - Tian Y
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Jiang, Dandan
AU  - Jiang D
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Ren, Jinrui
AU  - Ren J
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Li, Ziyong
AU  - Li Z
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Ding, Xiuliang
AU  - Ding X
AD  - Animal Nutrition Institute, Chongqing Academy of Animal Sciences, Chongqing, 
      China.
FAU - Zhang, Quanfang
AU  - Zhang Q
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Yoo, Dongwan
AU  - Yoo D
AUID- ORCID: 0000-0002-6730-9729
AD  - Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, 
      Illinois, USA.
FAU - Miller, Laura C
AU  - Miller LC
AD  - Department of Diagnostic Medicine and Pathobiology, College of Veterinary 
      Medicine, Kansas State University, Manhattan, Kansas, USA.
FAU - Lee, Changhee
AU  - Lee C
AD  - College of Veterinary Medicine and Virus Vaccine Research Center, Gyeongsang 
      National University, Jinju, Republic of Korea.
FAU - Cong, Xiaoyan
AU  - Cong X
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Li, Juntong
AU  - Li J
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Du, Yijun
AU  - Du Y
AUID- ORCID: 0000-0001-9215-4637
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
FAU - Qi, Jing
AU  - Qi J
AUID- ORCID: 0000-0002-5688-5579
AD  - Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of 
      Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and 
      Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of 
      Agricultural Sciences, Jinan, Shandong, China.
LA  - eng
GR  - ZR2021ZD08, R2020KC005, ZR2021MC139, ZR2023MC076/| Natural Science Foundation of 
      Shandong Province ()/
GR  - 32373094, 32102710/MOST | National Natural Science Foundation of China (NSFC)/
GR  - CXGC2023A21, CXGC2023G03/the Agricultural Scienfitic and Technological Innovation 
      Project of Shandong Academy of Agricultural Sciences/
GR  - 2018-67015-28287, 2023-67015-39710/U.S. Department of Agriculture (USDA)/
PT  - Journal Article
DEP - 20240304
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 9008-11-1 (Interferons)
RN  - 0 (Myxovirus Resistance Proteins)
RN  - 0 (Viral Nonstructural Proteins)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Interferons/immunology/metabolism
MH  - Mutation
MH  - *Myxovirus Resistance Proteins/chemistry/genetics/metabolism
MH  - *Porcine Reproductive and Respiratory Syndrome/enzymology/metabolism/virology
MH  - *Porcine respiratory and reproductive syndrome virus/growth & 
      development/metabolism
MH  - Protein Binding
MH  - Swine/virology
MH  - *Viral Nonstructural Proteins/antagonists & inhibitors/metabolism
MH  - *Virus Replication
PMC - PMC11019876
OTO - NOTNLM
OT  - Mx1
OT  - antiviral agents
OT  - interferons
OT  - porcine reproductive and respiratory syndrome virus
COIS- The authors declare no conflict of interest.
EDAT- 2024/03/04 12:47
MHDA- 2024/04/17 06:42
PMCR- 2024/03/04
CRDT- 2024/03/04 09:48
PHST- 2024/04/17 06:42 [medline]
PHST- 2024/03/04 12:47 [pubmed]
PHST- 2024/03/04 09:48 [entrez]
PHST- 2024/03/04 00:00 [pmc-release]
AID - 01844-23 [pii]
AID - jvi.01844-23 [pii]
AID - 10.1128/jvi.01844-23 [doi]
PST - ppublish
SO  - J Virol. 2024 Apr 16;98(4):e0184423. doi: 10.1128/jvi.01844-23. Epub 2024 Mar 4.