1. Academic Validation
  2. Peste Des Petits Ruminants Virus N Protein Is a Critical Proinflammation Factor That Promotes MyD88 and NLRP3 Complex Assembly

Peste Des Petits Ruminants Virus N Protein Is a Critical Proinflammation Factor That Promotes MyD88 and NLRP3 Complex Assembly

  • J Virol. 2022 May 25;96(10):e0030922. doi: 10.1128/jvi.00309-22.
Lingxia Li  # 1 Wenping Yang  # 1 Xiaoxia Ma 2 Jinyan Wu 1 Xiaodong Qin 1 Xiaoan Cao 1 Jianhua Zhou 2 Li Jin 2 Jijun He 1 Haixue Zheng 1 Xiangtao Liu 1 Dan Li 1 Youjun Shang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Veterinary Etiological Biology and OIE/National Foot and Mouth Disease Reference Laboratory, African swine fever Regional Laboratory of China, Lanzhou Veterinary Research Institutegrid.454892.6, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, China.
  • 2 Biomedical Research Center, Northwest Minzu University, Lanzhou, Gansu, China.
  • # Contributed equally.
Abstract

Inflammatory responses play a central role in host defense against invading pathogens. Peste des petits ruminants virus (PPRV) causes highly contagious acute or subacute disease of small ruminants. However, the precise mechanism by which PPRV regulates inflammatory responses remains unknown. Here, we revealed a novel mechanism by which PPRV induces inflammation. Our study showed that PPRV induced the secretion of interleukin 1β (IL-1β) by activating the NF-κB signaling pathway and the NLRP3 inflammasome. Moreover, PPRV replication and protein synthesis were essential for NLRP3 inflammasome activation. Importantly, PPRV N protein promoted NF-κB signaling pathway and NLRP3 inflammasome via direct binding of MyD88 and NLPR3, respectively, and induced Caspase-1 cleavage and IL-1β maturation. Biochemically, N protein interacted with MyD88 to potentiate the assembly of MyD88 complex and interacted with NLPR3 to facilitate NLRP3 inflammasome complex assembly by forming an N-NLRP3-ASC ring-like structure, leading to IL-1β secretion. These findings demonstrate a new function of PPRV N protein as an important proinflammation factor and identify a novel underlying mechanism modulating inflammasome assembly and function induced by PPRV. IMPORTANCE An important part of the innate immune response is the activation of NF-κB signaling pathway and NLPR3 inflammasome, which is induced upon exposure to pathogens. Peste des petits ruminants virus (PPRV) is a highly contagious virus causing fever, stomatitis, and pneumoenteritis in goats by inducing many proinflammatory cytokines. Although the NF-κB signaling pathway and NLRP3 inflammasome play an important role in regulating host immunity and viral Infection, the precise mechanism by which PPRV regulates inflammatory responses remains unknown. This study demonstrates that PPRV induces inflammatory responses. Mechanistically, PPRV N protein facilitates the MyD88 complex assembly by directly binding to MyD88 and promotes the NLRP3 inflammasome complex assembly by directly binding to NLRP3 to form ring-like structures of N-NLRP3-ASC. These findings provide insights into the prevention and treatment of PPRV Infection.

Keywords

IL-1β; N protein; NF-κB; NLRP3 inflammasome; PPRV.

Figures
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  • HY-P1009
    ≥98.0%, Caspase 1/4 抑制剂