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

Tiantian Zhou, Juan Xiong, Xuewen Hu, Yuanjiao Du, Anbing Shi, Weiping Chang, Jichao Qin, Lin Deng and Wei-Ke Ji ()
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Tiantian Zhou: Huazhong University of Science and Technology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongii Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic infectious Diseases
Juan Xiong: Huazhong University of Science and Technology, Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College
Xuewen Hu: Huazhong University of Science and Technology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongii Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic infectious Diseases
Yuanjiao Du: Shenzhen Bay Laboratory
Anbing Shi: Huazhong University of Science and Technology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongii Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic infectious Diseases
Weiping Chang: Shenzhen Bay Laboratory
Jichao Qin: Zhejiang University School of Medicine, Department of Gastrointestinal Surgery, the First Affiliated Hospital
Lin Deng: Shenzhen Bay Laboratory
Wei-Ke Ji: Huazhong University of Science and Technology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongii Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic infectious Diseases

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65540-2

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