Department of Molecular Biology, University of California, San Diego, La Jolla, California, United States of America.
Department of Immunology, University of Washington; Seattle, Washington, United States of America.
PLoS Biol. 2023 Jun 8;21(6):e3002144. doi: 10.1371/journal.pbio.3002144. eCollection 2023 Jun.
Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8's ability to sense coronavirus 3CLpros and, instead, enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology.
宿主进化出了多种策略来应对微生物感染，包括通过 NLRP1 和 CARD8 等炎症小体形成传感器检测病原体编码的蛋白酶。在这里，我们发现包括严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 在内的多种冠状病毒编码的 3CL 蛋白酶 (3CLpro) 可切割人类 CARD8 中一个快速进化的区域，并激活强烈的炎症小体反应。CARD8 在 SARS-CoV-2 感染过程中对于细胞死亡和促炎细胞因子的释放是必需的。我们进一步发现，自然变异改变了 CARD8 对 3CLpro 的感应，包括 3CLpro 介导的拮抗而非激活大蝙蝠 CARD8。同样，我们发现人类的一个单核苷酸多态性 (SNP) 降低了 CARD8 感应冠状病毒 3CLpros 的能力，而是使人类能够感应来自某些小核糖核酸病毒的 3C 蛋白酶 (3Cpro)。我们的研究结果表明，CARD8 是一种广泛的病毒蛋白酶活性传感器，并表明 CARD8 的多样性有助于炎症小体介导的病毒感应和免疫病理学的种间和种内变异。
