ZAK alpha-driven ribotoxic stress response activates the human NLRP1 inflammasome

Robinson, Kim S.; Toh, Gee Ann; Rozario, Pritisha; Chua, Rae; Bauernfried, Stefan; Sun, Zijin; Firdaus, Muhammad Jasrie; Bayat, Shima; Nadkarni, Rhea; Poh, Zhi Sheng; Tham, Khek Chian; Harapas, Cassandra R.; Lim, Chrissie K.; Chu, Werncui; Tay, Celest W. S.; Tan, Kiat Yi; Zhao, Tianyun; Bonnard, Carine; Sobota, Radoslaw; Connolly, John E.; Common, John; Masters, Seth L.; Chen, Kaiwen W.; Ho, Lena; Wu, Bin; Hornung, Veit und Zhong, Franklin L. (2022): ZAK alpha-driven ribotoxic stress response activates the human NLRP1 inflammasome. In: Science, Vol. 377, No. 6603: pp. 328-334

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 NLRPI (NLRP1(DR)) by MAP3K20/ZAK alpha kinase and its downstream effector, p38. Mutating a single ZAK alpha 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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 0036-8075
• Language: English