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

文献类型： 外文期刊

第一作者： Huang, Xiangyu

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

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：5.5； 五年影响因子：5.5 ）

ISSN： 1553-7366

年卷期： 2024 年 20 卷 7 期

页码：

收录情况： SCI

摘要： Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1 beta. Caspase-1 is involved in the maturation of IL-1 beta 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-1 beta and other IL-1 beta-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1 beta (sPro-IL-1 beta) exists as an oligomeric precursor unlike monomeric human Pro-IL-1 beta (hPro-IL-1 beta). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1 beta to produce mature IL-1 beta, while it cleaves hPro-IL-1 beta but does not produce mature IL-1 beta in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1 beta through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1 beta 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-1 beta (sIL-1 beta) generates a monomeric and active form of sIL-1 beta, initiating the downstream signaling. Thus, these studies provide IL-1 beta is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes. IL-1 beta is a key inflammatory mediator, crucial for immune responses and pathological inflammation. Upon the assembly of large complexes by NOD-like receptors, caspase-1 serves as the endogenous enzyme that cleaves pro-IL-1 beta in activate IL-1 beta. Previous studies have identified IL-1 beta is an innate immune sensor of group A Streptococcus (GAS) protease SpeB. However, whether IL-1 beta is an inflammatory sensor for viral proteases remains unclear. Here, we report that Seneca Valley Virus (SVV) 3C protease functions as an unconventional IL-1 beta-converting enzyme (ICE), specifically and directly cleaving and processing swine pro-IL-1 beta but not human pro-IL-1 beta. The cleaved IL-1 beta is bioactive, consistent with the function of mature IL-1 beta. This finding reveals a novel virus-mediated activation mechanism of IL-1 beta and may influence the host's inflammatory response.

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