Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome

• 成果类型: Article
• 署名作者: Rozario, Pritisha; Pinilla, Miriam; Gorse, Leana; Vind, Anna Constance; Robinson, Kim S.; Toh, Gee Ann; Firdaus, Muhammad Jasrie; Martinez, Jose Francisco; Kerk, Swat Kim; Lin, Zhewang; Chambers, John C.; Bekker-Jensen, Simon; Meunier, Etienne; Zhong, Franklin
• 署名单位: Nanyang Technological University; Centre National de la Recherche Scientifique (CNRS); Universite de Toulouse; University of Copenhagen; University of Copenhagen; Agency for Science Technology & Research (A*STAR); Agency for Science Technology & Research (A*STAR); Skin Research Institute of Singapore (SRIS); Nanyang Technological University; National University of Singapore; University of York - UK
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9157
• DOI: 10.1073/pnas.2309579121
• 发表日期: 2024-01-09
• 关键词: caspase-1 activation; inhibition; gramicidin; depletion; pathways; channel; trigger; toxins; pore; zak

摘要

Nigericin, an ionophore derived from Streptomyces hygroscopicus, is arguably the most commonly used tool compound to study the NLRP3 inflammasome. Recent findings, however, showed that nigericin also activates the NLRP1 inflammasome in human keratinocytes. In this study, we resolve the mechanistic basis of nigericin- driven NLRP1 inflammasome activation. In multiple nonhematopoietic cell types, nigericin rapidly and specifically inhibits the elongation stage of the ribosome cycle by depleting cytosolic potassium ions. This activates the ribotoxic stress response (RSR) sensor kinase ZAK alpha, p38, and JNK, as well as the hyperphosphorylation of the NLRP1 linker domain. As a result, nigericin- induced pyroptosis in human keratinocytes is blocked by extracellular potassium supplementation, ZAK alpha knockout, or pharmacologic inhibitors of ZAK alpha and p38 kinase activities. By surveying a panel of ionophores, we show that electroneutrality of ion movement is essential to activate ZAK alpha-driven RSR and a greater extent of K+ depletion is necessary to activate ZAK alpha-NLRP1 than NLRP3. These findings resolve the mechanism by which nigericin activates NLRP1 in nonhematopoietic cell types and demonstrate an unexpected connection between RSR, perturbations of potassium ion flux, and innate immunity.