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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; Zhong, Franklin L
Science, 07/2022, Letnik: 377, Številka: 6603Journal Article
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.
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in: SICRIS
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