Lipid transporters E-Syt3 and ORP5 regulate epithelial ion transport by controlling phosphatidylserine enrichment at ER/PM junctions

Lipid transporters E-Syt3 and ORP5 regulate epithelial ion transport by controlling phosphatidylserine enrichment at ER/PM junctions

Endoplasmic reticulum/plasma membrane (ER/PM) junctions are a major site of cellular signal transduction including in epithelia; however, whether their lipid membrane environment affects junctional ion transporters function remains unclear. Here, we show that epithelial secretion is governed by phos...

Teljes leírás

Elmentve itt :
Bibliográfiai részletek
Szerzők: Sarkar Paramita
Lüscher Benjamin P
Ye Zengyou
Chung Woo Young
Abtahi Ava Movahed
Zheng Changyu
Lee Min Goo
Varga Árpád
Pallagi Petra
Maléth József
Ahuja Malini
Muallem Shmuel
Dokumentumtípus: Cikk
Megjelent: 2025
Sorozat:EMBO JOURNAL
Tárgyszavak:
Klinikai orvostan
doi:10.1038/s44318-025-00470-9

mtmt:36169776
Online Access:http://publicatio.bibl.u-szeged.hu/36903
Leíró adatok
Tartalmi kivonat:Endoplasmic reticulum/plasma membrane (ER/PM) junctions are a major site of cellular signal transduction including in epithelia; however, whether their lipid membrane environment affects junctional ion transporters function remains unclear. Here, we show that epithelial secretion is governed by phosphatidylserine (PtdSer) levels in ER/PM nanodomains, specified by the antagonistic action of the lipid transfer proteins E-Syt3 and ORP5, which transduce cAMP signals to the chloride channel CFTR and activate the sodium-bicarbonate cotransporter NBCe1-B by IRBIT. Lipid transfer by E-Syt3, along with restricted plasma membrane localization by the E-Syt3 C2C domain, are essential for E-Syt3 function, as removal of PtdSer from junctions by E-Syt3 dissociated the cAMP signaling pathway complex, preventing CFTR activation, and prevented NBCe1-B activation by IRBIT. CFTR and NBCe1-B PtdSer sensor domains responded to PtdSer reduction by E-Syt3; which was reversed by exogenous PtdSer or by PtdSer supplied by ORP5. In mice, E-Syt3 depletion improved chloride flux and fluid secretion in salivary glands and isolated pancreatic ducts. These findings provide a framework for understanding the role of junctional lipids in the assembly of functional ion protein complexes and cellular communication at epithelial signaling hubs.
ISSN:0261-4189

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