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

• DOI: 10.1073/pnas.2309579121
• Publication Date: 2024-01-04T18:53:16Z
• Authors: Pritisha Rozario; Miriam Pinilla; Leana Gorse; Anna Constance Vind; Kim S. Robinson; Gee Ann Toh; Muhammad Jasrie F...; José Francisco Ma...; Swat Kim Kerk; Zhewang Lin; John C. Chambers; Simon Bekker-Jensen; Etienne Meunier; Franklin Zhong
• Keywords: Nigericin; Pyroptosis

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