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 (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.