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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Detalhes bibliográficos
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
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:2445/220715
Acesso em linha:https://hdl.handle.net/2445/220715
Access Level:Acceso aberto
Palavra-chave:Osmosi
Estrès (Fisiologia)
Canals de clorur
Osmosis
Stress (Physiology)
Chloride channels
Descrição
Resumo: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.

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