2. Academic Validation
  3. Duck hepatitis A virus 1-encoded 2B protein disturbs ion and organelle homeostasis to promote NF-κB/NLRP3-mediated inflammatory response

Duck hepatitis A virus 1-encoded 2B protein disturbs ion and organelle homeostasis to promote NF-κB/NLRP3-mediated inflammatory response

  • Int J Biol Macromol. 2024 Sep 23;280(Pt 3):135876. doi: 10.1016/j.ijbiomac.2024.135876.
Sai Mao 1,  Xinghong Liu 2,  Dandan Wu 2,  Zhilong Zhang 3,  Di Sun 4,  Xumin Ou 4,  Juan Huang 4,  Ying Wu 4,  Qiao Yang 4,  Bin Tian 4,  Shun Chen 5,  Mafeng Liu 5,  Dekang Zhu 5,  Shaqiu Zhang 5,  Xinxin Zhao 5,  Yu He 4,  Zhen Wu 4,  Renyong Jia 5,  Mingshu Wang 6,  Anchun Cheng 7
Affiliations

Affiliations

  • 1 Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, China; Engineering Research Center of Southwest Animal Disease Prevention and Control Technology, Ministry of Education of the People's Republic of China, Chengdu 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu 611130, China.
  • 2 Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
  • 3 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, China.
  • 4 Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; Engineering Research Center of Southwest Animal Disease Prevention and Control Technology, Ministry of Education of the People's Republic of China, Chengdu 611130, China.
  • 5 Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; Engineering Research Center of Southwest Animal Disease Prevention and Control Technology, Ministry of Education of the People's Republic of China, Chengdu 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu 611130, China.
  • 6 Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; Engineering Research Center of Southwest Animal Disease Prevention and Control Technology, Ministry of Education of the People's Republic of China, Chengdu 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu 611130, China. Electronic address: mshwang@163.com.
  • 7 Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; Engineering Research Center of Southwest Animal Disease Prevention and Control Technology, Ministry of Education of the People's Republic of China, Chengdu 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu 611130, China. Electronic address: chenganchun@vip.163.com.
PMID: 39322136 DOI: 10.1016/j.ijbiomac.2024.135876
Abstract

Previous studies by our group and Others have highlighted the critical role of hyperinflammation in the pathogenicity of duck hepatitis A virus 1 (DHAV-1), an avian picornavirus that has caused significant devastation in the duck industry worldwide for decades. However, the precise mechanisms by which DHAV-1 Infection regulates the inflammatory responses, particularly the production of IL-1β, remain poorly understood. In this study, we demonstrate that DHAV-1 Infection triggers NF-κB- and NLRP3 inflammasome-mediated IL-1β production. Mechanistically, DHAV-1 Infection, particularly its replication and translation, disrupts cellular homeostasis of CA2+, K+, ROS and Cathepsin, which act cooperatively as assembly signals for NLRP3 inflammasome activation. By screening DHAV-1-encoded proteins, we identified that the viroporin 2B dominates NF-κB as well as NLRP3 inflammasome activation. Mutation analysis revealed that I43 within the 2B protein is the key amino acid for CA2+ mobilization and subsequent activation of NF-κB transcriptional activity and NLRP3 inflammasome. Moreover, DHAV-1 Infection and the 2B protein activate the MAVS- and MyD88-NF-κB pathways by relay, providing the necessary priming signals for NLRP3 inflammasome activation. In summary, our findings elucidate a mechanism through which DHAV-1 triggers inflammatory responses via NF-κB/NLRP3 inflammasome activation, offering new perspectives on DHAV-1 pathogenesis and informing the development of targeted anti-DHAV-1 treatments.

Keywords

2B protein; Duck hepatitis A virus 1; Intracellular dyshomeostasis; NLRP3 inflammasome.

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