Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
The A*STAR Skin Research Labs , Singapore, Singapore.
J Exp Med. 2023 Oct 2;220(10). doi: 10.1084/jem.20230105. Epub 2023 Aug 29.
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.
ZAKα 驱动的核糖体毒性应激反应 (RSR) 是由核糖体停滞和/或碰撞激活的。最近的工作表明，RSR 还通过激活人类 NLRP1 炎性体在先天免疫中发挥作用。在这里，我们报告 ZAKα 和 NLRP1 感知靶向核糖体延伸因子的细菌外毒素。一种这样的毒素，白喉毒素 (DT)，是人类白喉的病原体，在原代人角质形成细胞中触发依赖 RSR 的炎性体激活。这个过程需要细菌中铁介导的 DT 产生，以及宿主细胞中二氢喋呤合成和 ZAKα/p38 驱动的 NLRP1 磷酸化。NLRP1 缺失消除了 DT 中毒角质形成细胞中 IL-1β 和 IL-18 的分泌，而 ZAKα 缺失或抑制此外还限制了细胞焦亡和炎性体非依赖性非细胞焦亡性细胞死亡。因此，在皮肤白喉的 3D 皮肤模型中，ZAKα 抑制的药理学抑制比 caspase-1 抑制更有效地保护表皮屏障。总之，这些发现表明 ZAKα 驱动的 RSR 和 NLRP1 炎性体参与了抗菌免疫，并可能解释了白喉发病机制的某些方面。
