LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions

Regulation of cell volume is essential for tissue homeostasis and cell viability. In response to hypertonic stress, cells need rapid electrolyte influx to compensate water loss and to prevent cell death in a process known as regulatory volume increase (RVI). However, the molecular component able to...

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Autores: Serra, Selma A., Stojakovic, Predrag, Amat, Ramon, Rubio Moscardó, Fanny, Latorre Doménech, Pablo, 1993-, Seisenbacher, Gerhard, Canadell, David, Böttcher, René, Aregger, Michael, Moffat, Jason, Nadal Clanchet, Eulàlia de, Valverde, M. A. (Miguel Ángel), 1963-, Posas Garriga, Francesc
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2021
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/48308
Acesso em linha:http://hdl.handle.net/10230/48308
http://dx.doi.org/10.1073/pnas.2025013118
Access Level:Acceso aberto
Palavra-chave:LRRC8A chloride channel
NKCC
RVI
Osmostress
p38/MSK1
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oai_identifier_str oai:recercat.cat:10230/48308
network_acronym_str ES
network_name_str España
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spelling LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditionsSerra, Selma A.Stojakovic, PredragAmat, RamonRubio Moscardó, FannyLatorre Doménech, Pablo, 1993-Seisenbacher, GerhardCanadell, DavidBöttcher, RenéAregger, MichaelMoffat, JasonNadal Clanchet, Eulàlia deValverde, M. A. (Miguel Ángel), 1963-Posas Garriga, FrancescLRRC8A chloride channelNKCCRVIOsmostressp38/MSK1Regulation of cell volume is essential for tissue homeostasis and cell viability. In response to hypertonic stress, cells need rapid electrolyte influx to compensate water loss and to prevent cell death in a process known as regulatory volume increase (RVI). However, the molecular component able to trigger such a process was unknown to date. Using a genome-wide CRISPR/Cas9 screen, we identified LRRC8A, which encodes a chloride channel subunit, as the gene most associated with cell survival under hypertonic conditions. Hypertonicity activates the p38 stress-activated protein kinase pathway and its downstream MSK1 kinase, which phosphorylates and activates LRRC8A. LRRC8A-mediated Cl- efflux facilitates activation of the with-no-lysine (WNK) kinase pathway, which in turn, promotes electrolyte influx via Na+/K+/2Cl- cotransporter (NKCC) and RVI under hypertonic stress. LRRC8A-S217A mutation impairs channel activation by MSK1, resulting in reduced RVI and cell survival. In summary, LRRC8A is key to bidirectional osmotic stress responses and cell survival under hypertonic conditions.This work was supported by grants from the Ministry of Science, Innovation, and Universities (PGC2018-094136-B-I00 to F.P.; BFU2017-85152-P and Fondo Europeo de Desarrollo Regional [FEDER] to E.d.N.; RTI2018-099718-B-I00 and FEDER to M.A.V.), the Catalan Government (2017 SGR 799), the Fundación Botín, and the Banco Santander through its Santander Universities Global Division to F.P. We gratefully acknowledge institutional funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award and from the Centres de Recerca de Catalunya (CERCA) Programme of the Catalan Government and the Unidad de Excelencia María de Maeztu, funded by the Agencia Estatal de Investigación (AEI) (CEX2018-000792-M). F.P. and E.d.N. are recipients of an Institució Catalana de Recerca i Estudis Avançats (ICREA) Acadèmia award (Generalitat de Catalunya).National Academy of Sciences202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/48308http://dx.doi.org/10.1073/pnas.2025013118reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésProc Natl Acad Sci U S A. 2021;118(23):e2025013118info:eu-repo/grantAgreement/ES/2PE/PGC2018-094136-B-I00info:eu-repo/grantAgreement/ES/2PE/BFU2017-85152-P© 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/483082026-05-29T05:05:01Z
dc.title.none.fl_str_mv LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
title LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
spellingShingle LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
Serra, Selma A.
LRRC8A chloride channel
NKCC
RVI
Osmostress
p38/MSK1
title_short LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
title_full LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
title_fullStr LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
title_full_unstemmed LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
title_sort LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
dc.creator.none.fl_str_mv Serra, Selma A.
Stojakovic, Predrag
Amat, Ramon
Rubio Moscardó, Fanny
Latorre Doménech, Pablo, 1993-
Seisenbacher, Gerhard
Canadell, David
Böttcher, René
Aregger, Michael
Moffat, Jason
Nadal Clanchet, Eulàlia de
Valverde, M. A. (Miguel Ángel), 1963-
Posas Garriga, Francesc
author Serra, Selma A.
author_facet Serra, Selma A.
Stojakovic, Predrag
Amat, Ramon
Rubio Moscardó, Fanny
Latorre Doménech, Pablo, 1993-
Seisenbacher, Gerhard
Canadell, David
Böttcher, René
Aregger, Michael
Moffat, Jason
Nadal Clanchet, Eulàlia de
Valverde, M. A. (Miguel Ángel), 1963-
Posas Garriga, Francesc
author_role author
author2 Stojakovic, Predrag
Amat, Ramon
Rubio Moscardó, Fanny
Latorre Doménech, Pablo, 1993-
Seisenbacher, Gerhard
Canadell, David
Böttcher, René
Aregger, Michael
Moffat, Jason
Nadal Clanchet, Eulàlia de
Valverde, M. A. (Miguel Ángel), 1963-
Posas Garriga, Francesc
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv LRRC8A chloride channel
NKCC
RVI
Osmostress
p38/MSK1
topic LRRC8A chloride channel
NKCC
RVI
Osmostress
p38/MSK1
description Regulation of cell volume is essential for tissue homeostasis and cell viability. In response to hypertonic stress, cells need rapid electrolyte influx to compensate water loss and to prevent cell death in a process known as regulatory volume increase (RVI). However, the molecular component able to trigger such a process was unknown to date. Using a genome-wide CRISPR/Cas9 screen, we identified LRRC8A, which encodes a chloride channel subunit, as the gene most associated with cell survival under hypertonic conditions. Hypertonicity activates the p38 stress-activated protein kinase pathway and its downstream MSK1 kinase, which phosphorylates and activates LRRC8A. LRRC8A-mediated Cl- efflux facilitates activation of the with-no-lysine (WNK) kinase pathway, which in turn, promotes electrolyte influx via Na+/K+/2Cl- cotransporter (NKCC) and RVI under hypertonic stress. LRRC8A-S217A mutation impairs channel activation by MSK1, resulting in reduced RVI and cell survival. In summary, LRRC8A is key to bidirectional osmotic stress responses and cell survival under hypertonic conditions.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/48308
http://dx.doi.org/10.1073/pnas.2025013118
url http://hdl.handle.net/10230/48308
http://dx.doi.org/10.1073/pnas.2025013118
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Proc Natl Acad Sci U S A. 2021;118(23):e2025013118
info:eu-repo/grantAgreement/ES/2PE/PGC2018-094136-B-I00
info:eu-repo/grantAgreement/ES/2PE/BFU2017-85152-P
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.228081

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