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., Ho L., Wu B., Hornung V., Zhong FL.
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.