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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.

Original publication

DOI

10.1126/science.abl6324

Type

Journal article

Journal

Science (New York, N.Y.)

Publication Date

07/2022

Volume

377

Pages

328 - 335

Addresses

Skin Research Institute of Singapore (SRIS), 308232 Singapore.

Keywords

Ribosomes, Keratinocytes, Humans, Anisomycin, MAP Kinase Kinase Kinases, Neoplasm Proteins, Ultraviolet Rays, Phosphorylation, Mutation, CARD Signaling Adaptor Proteins, Stress, Physiological, Inflammasomes, Pyroptosis, NLR Proteins