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

文献类型： 外文期刊

作者： Xiangyu Huang;Zhenchao Zhao;Cheng Zhu;Lvye Chai;Ya Yan;Ye Yuan;Lei Wu;Minjie Li;Xiaohan Jiang;Haiwei Wang;Zheng Liu;Pingwei Li;Xin Li

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期刊名称： PLoS Pathogens

ISSN： 1553-7366

年卷期： 2024 年 20 卷 7 July 期

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收录情况： SCIE（2024版）

摘要： 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 swine IL-1β (sIL-1β) generates a monomeric and active form of sIL-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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