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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月27日

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  • Paramita Sarkar,
  • Benjamin P Lüscher,
  • Zengyou Ye,
  • Woo Young Chung,
  • Ava Movahed Abtahi,
  • Changyu Zheng,
  • Min Goo Lee,
  • Árpád Varga,
  • Petra Pallagi,
  • József Maléth,
  • Malini Ahuja,
  • Shmuel Muallem

摘要

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.