The Role of the LRRC8A anion channel in adaptation to stress
Cell volume regulation is essential for cellular homeostasis and adaptation to environmental osmotic changes. Upon hyperosmotic stress, cells need to rapidly restore osmotic balances in order to preserve the function of essential cellular processes and activate the adaptive responses to maximize cel...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/687886 |
| Acceso en línea: | http://hdl.handle.net/10803/687886 |
| Access Level: | acceso abierto |
| Palabra clave: | Stress LRRC8A p38/MSK1 WNK1/NKCC1 RVI Estrés 577 |
| Sumario: | Cell volume regulation is essential for cellular homeostasis and adaptation to environmental osmotic changes. Upon hyperosmotic stress, cells need to rapidly restore osmotic balances in order to preserve the function of essential cellular processes and activate the adaptive responses to maximize cell survival. By using a genome-wide CRSIPR/Cas9 screening, we identified LRRC8A gene, encoding the main subunit of the LRRC8A anion channel, to be required for survival of HeLa cells under hyperosmotic conditions. The LRRC8A channel is activated by phosphorylation at the S217 via the p38 MAPK-MSK1/2 pathway. The chloride efflux mediated by activated LRRC8A anion channel is required for reduction of the intracellular chloride concentration in cells exposed to cells. The ubiquitously expressed WNK1 is a chloride-sensitive kinase activated by hyperosmotic stress that regulates electrolyte influx by NKCC1, a main effector of regulated volume increase (RVI) process. LRRC8A deletion, pharmacological inhibition or impaired phosphorylation of LRRC8A S217A prevented WNK1-NKCC1 activation, RVI and impaired survival, thus demonstrating the relevance of channel activity and its regulation by this phosphorylation mechanism upon hyperosmotic stress. |
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