Skin Research Institute of Singapore (SRIS), 308232 Singapore.
Agency for Science, Technology and Research (A*STAR) Skin Research Laboratories (ASRL), 138648 Singapore.
Science. 2022 Jul 15;377(6603):328-335. doi: 10.1126/science.abl6324. Epub 2022 Jul 14.
Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1 abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1 to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.
人类 NLRP1（NACHT、LRR 和 PYD 结构域蛋白 1）是一种主要在皮肤和气道上皮细胞中表达的先天免疫传感器。在这里，我们报告人类 NLRP1 感知紫外线 B（UVB）和毒素诱导的核糖体毒性应激反应（RSR）。从生物化学角度来看，RSR 导致 MAP3K20/ZAKα 激酶及其下游效应物 p38 直接使人类 NLRP1（NLRP1）的特异性无序连接区发生过度磷酸化。突变 NLRP1 中的单个 ZAKα 磷酸化位点可消除 UVB 和核糖体毒素驱动的人角质形成细胞中的细胞焦亡。此外，将 NLRP1 与 CARD8 融合，CARD8 本身对 RSR 不敏感，可创建一个对 UVB 和核糖体毒素具有最小反应性的炎症小体传感器。这些结果深入了解了人类皮肤角质形成细胞对 UVB 的感知，确定了几种核糖体毒素是 NLRP1 的激动剂，并确立了炎症小体驱动的细胞焦亡是 RSR 的一个组成部分。
