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

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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
    Huazhong University of Science and Technology, Cell Architecture Research Center)

  • 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
    Shenzhen Bay Laboratory
    Huazhong University of Science and Technology, Cell Architecture Research Center)

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.

Suggested Citation

  • Tiantian Zhou & Juan Xiong & Xuewen Hu & Yuanjiao Du & Anbing Shi & Weiping Chang & Jichao Qin & Lin Deng & Wei-Ke Ji, 2025. "Sec14L6 is a phosphoinositide transporter that regulates phosphoinositide homeostasis and biogenesis of lipid droplets," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65540-2
    DOI: 10.1038/s41467-025-65540-2
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