ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

Science. 2022 Jul 15;377(6603):328-335. doi: 10.1126/science.abl6324.

Kim S Robinson ¹ ², Gee Ann Toh ³, Pritisha Rozario ³, Rae Chua ³, Stefan Bauernfried ⁴ ⁵, Zijin Sun ³, Muhammad Jasrie Firdaus ³, Shima Bayat ³, Rhea Nadkarni ⁶, Zhi Sheng Poh ³, Khek Chian Tham ², Cassandra R Harapas ⁷, Chrissie K Lim ⁸ ⁹, Werncui Chu ⁶, Celest W S Tay ³, Kiat Yi Tan ², Tianyun Zhao ⁸, Carine Bonnard ¹ ², Radoslaw Sobota ⁸, John E Connolly ⁸, John Common ², Seth L Masters ⁷ ¹⁰, Kaiwen W Chen ¹¹, Lena Ho ⁶ ⁸, Bin Wu ¹², Veit Hornung ⁴ ⁵, Franklin L Zhong ¹ ³

Affiliations

1 Skin Research Institute of Singapore (SRIS), 308232 Singapore.
2 Agency for Science, Technology and Research (A*STAR) Skin Research Laboratories (ASRL), 138648 Singapore.
3 Lee Kong Chian School of Medicine, Nanyang Technological University, 308232 Singapore.
4 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
5 Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany.
6 Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, 169857 Singapore.
7 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
8 Institute of Molecular and Cell Biology, A*STAR, 138673 Singapore.
9 Present address: MiroBio Limited, Oxford OX4 4GE, UK.
10 Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
11 Immunology Translational Research Programme and Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117545 Singapore.
12 School of Biological Sciences, Nanyang Technological University (NTU), 639798 Singapore.

PMID: 35857590 DOI: 10.1126/science.abl6324

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 (NLRP1^DR) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα 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.

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