K. Robinson, G. Toh, P. Rozario, Rae Chua, Stefan Bauernfried, Zijin Sun, Muhammad Jasrie Firdaus, Shima Bayat, R. Nadkarni, Z. Poh, K. Tham, C. Harapas, Chrissie K. Lim, Werncui Chu, Celest W. S. Tay, K. Tan, T. Zhao, C. Bonnard, R. Sobota, J. Connolly, J. Common, S. Masters, Kaiwen W. Chen, L. Ho, Bin Wu, V. Hornung, F. Zhong
Science · 2022
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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 (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. Description Sunburn: a ZAK attack Nod-like receptors (NLRs) are intracellular sensors of infection that, when activated, assemble into signaling complexes (inflammasomes) that induce proinflammatory cytokine production and pyroptotic cell death. One such NLR, NLRP1, is expressed in the skin and can be triggered by ultraviolet B (UVB) radiation, the cause of acute sunburn. Robinson et al. report that UVB-induced RNA photolesions stall ribosomes, activating the ribotoxic stress response kinase ZAKα. Together with p38, ZAKα directly phosphorylates the disordered linker region of human NLRP1. Several microbial ribotoxins also trigger this pathway, suggesting that it may serve as a target for future anti-inflammatory therapies. —STS Part of the human inflammasome, an innate immune sensor complex, senses the ribotoxic stress response.