炎症体
上睑下垂
白喉毒素
微生物学
生物
半胱氨酸蛋白酶1
细胞生物学
毒素
免疫学
炎症
作者
Kim Robinson,Gee Ann Toh,Muhammad Jasrie Firdaus,Khek‐Chian Tham,Pritisha Rozario,Chrissie Lim,Ying Xiu Toh,Zhi Heng Lau,Sophie Charlotte Binder,Jacob Mayer,Carine Bonnard,Florian I. Schmidt,John E.A. Common,Franklin L. Zhong
摘要
The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity by activating the human NLRP1 inflammasome. Here, we report that ZAKα and NLRP1 sense bacterial exotoxins that target ribosome elongation factors. One such toxin, diphtheria toxin (DT), the causative agent for human diphtheria, triggers RSR-dependent inflammasome activation in primary human keratinocytes. This process requires iron-mediated DT production in the bacteria, as well as diphthamide synthesis and ZAKα/p38-driven NLRP1 phosphorylation in host cells. NLRP1 deletion abrogates IL-1β and IL-18 secretion by DT-intoxicated keratinocytes, while ZAKα deletion or inhibition additionally limits both pyroptotic and inflammasome-independent non-pyroptotic cell death. Consequently, pharmacologic inhibition of ZAKα is more effective than caspase-1 inhibition at protecting the epidermal barrier in a 3D skin model of cutaneous diphtheria. In summary, these findings implicate ZAKα-driven RSR and the NLRP1 inflammasome in antibacterial immunity and might explain certain aspects of diphtheria pathogenesis.
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