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

Autor:	Rozario P; Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore., Pinilla M; Institute of Pharmacology and Structural Biology, University of Toulouse, CNRS, Toulouse 31077, France., Gorse L; Institute of Pharmacology and Structural Biology, University of Toulouse, CNRS, Toulouse 31077, France., Vind AC; Center for Healthy Aging, University of Copenhagen, Copenhagen 2200, Denmark.; Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen 2200, Denmark., Robinson KS; Agency for Science, Technology and Research (A*STAR) Skin Research Labs, 138648, Singapore.; Skin Research Institute of Singapore, 308232, Singapore., Toh GA; Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore., Firdaus MJ; Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore., Martínez JF; Center for Healthy Aging, University of Copenhagen, Copenhagen 2200, Denmark.; Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen 2200, Denmark., Kerk SK; Population and Global Health Program, Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore., Lin Z; Department of Biological Sciences, National University of Singapore, 117543, Singapore., Chambers JC; Population and Global Health Program, Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore., Bekker-Jensen S; Center for Healthy Aging, University of Copenhagen, Copenhagen 2200, Denmark.; Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen 2200, Denmark., Meunier E; Institute of Pharmacology and Structural Biology, University of Toulouse, CNRS, Toulouse 31077, France., Zhong F; Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore.; Skin Research Institute of Singapore, 308232, Singapore.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jan 09; Vol. 121 (2), pp. e2309579121. Date of Electronic Publication: 2024 Jan 04.
DOI:	10.1073/pnas.2309579121
Abstrakt:	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 ZAKα, 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, ZAKα knockout, or pharmacologic inhibitors of ZAKα and p38 kinase activities. By surveying a panel of ionophores, we show that electroneutrality of ion movement is essential to activate ZAKα-driven RSR and a greater extent of K+ depletion is necessary to activate ZAKα-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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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