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Sec14L6 is a phosphoinositide transporter that regulates phosphoinositide homeostasis and biogenesis of lipid droplets.

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Titel: Sec14L6 is a phosphoinositide transporter that regulates phosphoinositide homeostasis and biogenesis of lipid droplets.
Autoren: Zhou, Tiantian, Xiong, Juan, Hu, Xuewen, Du, Yuanjiao, Shi, Anbing, Chang, Weiping, Qin, Jichao, Deng, Lin, Ji, Wei-Ke
Quelle: Nature Communications; 11/26/2025, Vol. 16 Issue 1, p1-21, 21p
Abstract: Lipid droplets (LDs) are evolutionarily conserved organelles essential for cellular metabolism. They form and grow at the endoplasmic reticulum (ER), requiring lipid transfer between these compartments, yet the underlying molecular mechanisms remain elusive. We identify Sec14L6, a unique Sec14 family member, as a lipid transporter regulating phosphoinositide (PIP) homeostasis and LD biogenesis, promoting adipogenic differentiation of mesenchymal stem cells. Sec14L6 directly binds the LD biogenesis factor ACSL3, which facilitates the association of Sec14L6 with LD surface. Furthermore, the ER membrane protein PGRMC1 recruits Sec14L6 to the ER. Targeted lipidomics revealed profound PIP dysregulation in Sec14L6-KO cells: LDs accumulated phosphoinositide-4-phosphate (PI4P) and PI(4,5)P₂, while these PIPs were reduced within the ER. In vitro assays demonstrated that Sec14L6 transports PI4P and PI(4,5)P₂. Sec14L6 knockout significantly impaired LD formation; this defect was rescued by wild-type Sec14L6, but not by lipid-transfer-deficient mutants. Our study reveals an essential role for Sec14L6 in PIP homeostasis and promotes LD biogenesis through lipid transfer between the ER and LDs. This study identifies Sec14L6 as a crucial lipid transporter that balances phosphoinositide levels between the endoplasmic reticulum and lipid droplets, thereby promoting the formation of lipid droplets and driving fat cell differentiation. [ABSTRACT FROM AUTHOR]
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Datenbank: Complementary Index
Beschreibung
Abstract:Lipid droplets (LDs) are evolutionarily conserved organelles essential for cellular metabolism. They form and grow at the endoplasmic reticulum (ER), requiring lipid transfer between these compartments, yet the underlying molecular mechanisms remain elusive. We identify Sec14L6, a unique Sec14 family member, as a lipid transporter regulating phosphoinositide (PIP) homeostasis and LD biogenesis, promoting adipogenic differentiation of mesenchymal stem cells. Sec14L6 directly binds the LD biogenesis factor ACSL3, which facilitates the association of Sec14L6 with LD surface. Furthermore, the ER membrane protein PGRMC1 recruits Sec14L6 to the ER. Targeted lipidomics revealed profound PIP dysregulation in Sec14L6-KO cells: LDs accumulated phosphoinositide-4-phosphate (PI4P) and PI(4,5)P₂, while these PIPs were reduced within the ER. In vitro assays demonstrated that Sec14L6 transports PI4P and PI(4,5)P₂. Sec14L6 knockout significantly impaired LD formation; this defect was rescued by wild-type Sec14L6, but not by lipid-transfer-deficient mutants. Our study reveals an essential role for Sec14L6 in PIP homeostasis and promotes LD biogenesis through lipid transfer between the ER and LDs. This study identifies Sec14L6 as a crucial lipid transporter that balances phosphoinositide levels between the endoplasmic reticulum and lipid droplets, thereby promoting the formation of lipid droplets and driving fat cell differentiation. [ABSTRACT FROM AUTHOR]
ISSN:20411723
DOI:10.1038/s41467-025-65540-2