ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

Robinson, KS; Toh, GA; Rozario, P; Chua, R; Bauernfried, S; Sun, Z; Firdaus, MJ; Bayat, S; Nadkarni, R; Poh, ZS; Tham, KC; Harapas, CR; Lim, CK; Chu, W; Tay, CWS; Tan, KY; Zhao, T; Bonnard, C; Sobota, R; Connolly, JE; Common, J; Masters, SL; Chen, KW; Ho, L; Wu, B; Hornung, V; Zhong, FL

Author(s): Robinson, KS; Toh, GA; Rozario, P; Chua, R; Bauernfried, S; Sun, Z; Firdaus, MJ; Bayat, S; Nadkarni, R; Poh, ZS; Tham, KC; Harapas, CR; Lim, CK; Chu, W; Tay, CWS; Tan, KY; Zhao, T; Bonnard, C; Sobota, R; Connolly, JE; Common, J; Masters, SL; Chen, KW; Ho, L; Wu, B; Hornung, V; Zhong, FL;
Details: Publication Year 2022-07-15,Volume 377,Issue #6603,Page 328-335
Journal Title: Science
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 (NLRP1(DR)) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1(DR) abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1(DR) 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.
Publisher: AAAS
Research Division(s): Inflammation
PubMed ID: 35857590/
Publisher's Version: https://doi.org/10.1126/science.abl6324
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2022-07-22 09:06:36

Last Modified: 2022-07-22 09:12:13