新加坡南洋理工大学Franklin L. Zhong团队近期取得重要工作进展，他们研究发现ZAKα驱动的核素毒素应激反应激活人类NLRP1炎症小体。该项研究成果2022年7月15日在线发表于《科学》杂志上。

在这里，研究人员报告了人类NLRP1感知紫外线B（UVB）和毒素诱导的核糖毒素应激反应（RSR）。 在生化方面，RSR 导致 NLRP1 的人类特异性无序连接区域（NLRP1^DR）被MAP3K20/ZAKα 激酶及其下游效应器p38直接过度磷酸化。在NLRP1^DR中的一个ZAKα磷酸化位点发生突变，会使人类角质细胞中的UVB和核糖毒素驱动的细胞焦亡现象消失。

此外，将NLRP1^DR与本身对RSR不敏感的CARD8融合，为UVB和核毒素创建了一个最小的炎性体传感器。 这些结果为人类皮肤角质细胞感知UVB提供了深入的见解，确定了几种核毒素作为NLRP1激动剂，并将炎症小体驱动的细胞焦亡确定为RSR的一个组成部分。

据介绍，人类NLRP1（NACHT, LRR和PYD结构域蛋白1）是一种先天免疫传感器，主要表达于皮肤和气道上皮细胞中。

附：英文原文

Title: ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

Author: Kim S. Robinson, Gee Ann Toh, Pritisha Rozario, Rae Chua, Stefan Bauernfried, Zijin Sun, Muhammad Jasrie Firdaus, Shima Bayat, Rhea Nadkarni, Zhi Sheng Poh, Khek Chian Tham, Cassandra R. Harapas, Chrissie K. Lim, Werncui Chu, Celest W. S. Tay, Kiat Yi Tan, Tianyun Zhao, Carine Bonnard, Radoslaw Sobota, John E. Connolly, John Common, Seth L. Masters, Kaiwen W. Chen, Lena Ho, Bin Wu, Veit Hornung, Franklin L. Zhong

Issue&Volume: 2022-07-15

Abstract: 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 (NLRP1DR) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1DR 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.

DOI: abl6324

Source: https://www.science.org/doi/10.1126/science.abl6324