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 Moscardo, Fanny, Latorre Domenech, Pablo, Seisenbacher, Gerhard, Canadell Sala, David, Böttcher, René, Aregger, Michael, Moffat, Jason, Nadal Clanchet, Eulàlia de, Valverde, Miguel A., Posas, Francesc
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/220715
Acesso em linha:https://hdl.handle.net/2445/220715
Access Level:acceso abierto
Palavra-chave:Osmosi
Estrès (Fisiologia)
Canals de clorur
Osmosis
Stress (Physiology)
Chloride channels
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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 Moscardo, FannyLatorre Domenech, PabloSeisenbacher, GerhardCanadell Sala, DavidBöttcher, RenéAregger, MichaelMoffat, JasonNadal Clanchet, Eulàlia deValverde, Miguel A.Posas, FrancescOsmosiEstrès (Fisiologia)Canals de clorurOsmosisStress (Physiology)Chloride channelsRegulation 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. LRRC8Amediated 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. LRRC8AS217A 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.National Academy of Sciences2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/220715Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1073/pnas.2025013118Proceedings of the National Academy of Sciences of the United States of America, 2021, vol. 118, num. 23https://doi.org/10.1073/pnas.2025013118cc-by-nc-nd (c) Serra, Selma A. et al., 2021http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2207152026-05-27T06:46:51Z
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.
Osmosi
Estrès (Fisiologia)
Canals de clorur
Osmosis
Stress (Physiology)
Chloride channels
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 Moscardo, Fanny
Latorre Domenech, Pablo
Seisenbacher, Gerhard
Canadell Sala, David
Böttcher, René
Aregger, Michael
Moffat, Jason
Nadal Clanchet, Eulàlia de
Valverde, Miguel A.
Posas, Francesc
author Serra, Selma A.
author_facet Serra, Selma A.
Stojakovic, Predrag
Amat, Ramon
Rubio Moscardo, Fanny
Latorre Domenech, Pablo
Seisenbacher, Gerhard
Canadell Sala, David
Böttcher, René
Aregger, Michael
Moffat, Jason
Nadal Clanchet, Eulàlia de
Valverde, Miguel A.
Posas, Francesc
author_role author
author2 Stojakovic, Predrag
Amat, Ramon
Rubio Moscardo, Fanny
Latorre Domenech, Pablo
Seisenbacher, Gerhard
Canadell Sala, David
Böttcher, René
Aregger, Michael
Moffat, Jason
Nadal Clanchet, Eulàlia de
Valverde, Miguel A.
Posas, Francesc
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Osmosi
Estrès (Fisiologia)
Canals de clorur
Osmosis
Stress (Physiology)
Chloride channels
topic Osmosi
Estrès (Fisiologia)
Canals de clorur
Osmosis
Stress (Physiology)
Chloride channels
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. LRRC8Amediated 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. LRRC8AS217A 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
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 https://hdl.handle.net/2445/220715
url https://hdl.handle.net/2445/220715
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1073/pnas.2025013118
Proceedings of the National Academy of Sciences of the United States of America, 2021, vol. 118, num. 23
https://doi.org/10.1073/pnas.2025013118
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Serra, Selma A. et al., 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Serra, Selma A. et al., 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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 Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406731262492672
score 15.223283

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