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

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Standard

Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome. / Rozario, Pritisha; Pinilla, Miriam; Gorse, Leana; Vind, Anna Constance; Robinson, Kim S.; Toh, Gee Ann; Firdaus, Muhammad Jasrie; Martínez, José Francisco; Kerk, Swat Kim; Lin, Zhewang; Chambers, John C.; Bekker-Jensen, Simon; Meunier, Etienne; Zhong, Franklin.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 121, Nr. 2, e2309579121, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Rozario, P, Pinilla, M, Gorse, L, Vind, AC, Robinson, KS, Toh, GA, Firdaus, MJ, Martínez, JF, Kerk, SK, Lin, Z, Chambers, JC, Bekker-Jensen, S, Meunier, E & Zhong, F 2024, 'Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome', Proceedings of the National Academy of Sciences of the United States of America, bind 121, nr. 2, e2309579121. https://doi.org/10.1073/pnas.2309579121

APA

Rozario, P., Pinilla, M., Gorse, L., Vind, A. C., Robinson, K. S., Toh, G. A., Firdaus, M. J., Martínez, J. F., Kerk, S. K., Lin, Z., Chambers, J. C., Bekker-Jensen, S., Meunier, E., & Zhong, F. (2024). Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome. Proceedings of the National Academy of Sciences of the United States of America, 121(2), [e2309579121]. https://doi.org/10.1073/pnas.2309579121

Vancouver

Rozario P, Pinilla M, Gorse L, Vind AC, Robinson KS, Toh GA o.a. Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome. Proceedings of the National Academy of Sciences of the United States of America. 2024;121(2). e2309579121. https://doi.org/10.1073/pnas.2309579121

Author

Rozario, Pritisha ; Pinilla, Miriam ; Gorse, Leana ; Vind, Anna Constance ; Robinson, Kim S. ; Toh, Gee Ann ; Firdaus, Muhammad Jasrie ; Martínez, José Francisco ; Kerk, Swat Kim ; Lin, Zhewang ; Chambers, John C. ; Bekker-Jensen, Simon ; Meunier, Etienne ; Zhong, Franklin. / Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome. I: Proceedings of the National Academy of Sciences of the United States of America. 2024 ; Bind 121, Nr. 2.

Bibtex

@article{8ce37f45bb7d4848b5544d6c90cf4bc9,
title = "Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome",
abstract = "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.",
keywords = "inflammasome, innate immunity, nigericin, NLRP1, potassium efflux",
author = "Pritisha Rozario and Miriam Pinilla and Leana Gorse and Vind, {Anna Constance} and Robinson, {Kim S.} and Toh, {Gee Ann} and Firdaus, {Muhammad Jasrie} and Mart{\'i}nez, {Jos{\'e} Francisco} and Kerk, {Swat Kim} and Zhewang Lin and Chambers, {John C.} and Simon Bekker-Jensen and Etienne Meunier and Franklin Zhong",
year = "2024",
doi = "10.1073/pnas.2309579121",
language = "English",
volume = "121",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "2",

}

RIS

TY - JOUR

T1 - Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome

AU - Rozario, Pritisha

AU - Pinilla, Miriam

AU - Gorse, Leana

AU - Vind, Anna Constance

AU - Robinson, Kim S.

AU - Toh, Gee Ann

AU - Firdaus, Muhammad Jasrie

AU - Martínez, José Francisco

AU - Kerk, Swat Kim

AU - Lin, Zhewang

AU - Chambers, John C.

AU - Bekker-Jensen, Simon

AU - Meunier, Etienne

AU - Zhong, Franklin

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - inflammasome

KW - innate immunity

KW - nigericin

KW - NLRP1

KW - potassium efflux

U2 - 10.1073/pnas.2309579121

DO - 10.1073/pnas.2309579121

M3 - Journal article

C2 - 38175865

AN - SCOPUS:85181632069

VL - 121

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

M1 - e2309579121

ER -

ID: 379651745