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

• Published in: PLoS pathogens Vol. 20; no. 7; p. e1012398
• Main Authors: Huang, Xiangyu, Zhao, Zhenchao, Zhu, Cheng, Chai, Lvye, Yan, Ya, Yuan, Ye, Wu, Lei, Li, Minjie, Jiang, Xiaohan, Wang, Haiwei, Liu, Zheng, Li, Pingwei, Li, Xin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2024; Public Library of Science (PLoS)
• Subjects: 3C Viral Proteases - metabolism; Alveoli; Animals; Biology and Life Sciences; Caspase-1; Caspase-4; Cell culture; Cell death; Chromatography; Cleavage; Cysteine Endopeptidases - metabolism; Enzymes; Humans; Hydrophobicity; IL-1β; Infections; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammation - metabolism; Interleukin 18; Interleukin-1beta - metabolism; Macrophages; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - virology; Medicine and Health Sciences; Molecular modelling; Morphology; Mutagenesis; Picornaviridae; Picornaviridae Infections - metabolism; Picornaviridae Infections - virology; Plasmids; Protease; Proteinase; Research and Analysis Methods; Species Specificity; Substrates; Swine; Viral infections; Viral Proteins - metabolism; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012398

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.