Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

  • PLoS Pathog. 2024 Jul 22;20(7):e1012398. doi: 10.1371/journal.ppat.1012398.
Xiangyu Huang  1  2 ,  Zhenchao Zhao  1  2 ,  Cheng Zhu  3 ,  Lvye Chai  1  2 ,  Ya Yan  1  2 ,  Ye Yuan  1  2 ,  Lei Wu  1  2 ,  Minjie Li  1  2 ,  Xiaohan Jiang  1  2 ,  Haiwei Wang  4 ,  Zheng Liu  5 ,  Pingwei Li  6 ,  Xin Li  1  2
Affiliations
  • 1. National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
  • 2. Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China.
  • 3. Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, China.
  • 4. State Key Laboratory of Animal Disease Control, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
  • 5. Koblika Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China.
  • 6. Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
PMID: 39038050 DOI: 10.1371/journal.ppat.1012398
Abstract

Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of Caspase-1 processing of pro-IL-1β and Other IL-1β-converting Enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an 'exosite' with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1β generates a monomeric and active form of IL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.

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