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The luminal domain region of Seipin/Fld1 is dispensable for establishing functional ER sites for lipid droplet biogenesis

Author

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  • Amit Khatri

    (All India Institute of Medical Sciences (AIIMS), Lipid Metabolism Laboratory, Department of Biotechnology)

  • Ritika Chaudhary

    (All India Institute of Medical Sciences (AIIMS), Lipid Metabolism Laboratory, Department of Biotechnology)

  • R. Mankamna Kumari

    (All India Institute of Medical Sciences (AIIMS), Lipid Metabolism Laboratory, Department of Biotechnology)

  • Vineet Choudhary

    (All India Institute of Medical Sciences (AIIMS), Lipid Metabolism Laboratory, Department of Biotechnology)

Abstract

Lipid droplet (LD) biogenesis occurs in the endoplasmic reticulum (ER), the mechanisms of which is not completely known. Seipin (Fld1 in yeast) is a crucial ER membrane protein that defines LD biogenesis sites. Here, we show that truncated seipin, Fld1-∆LR in yeast, and the human equivalent hSeipin-∆LR, mutants lacking the conserved luminal domain region (LR), functionally complement the LD biogenesis defect of fld1∆ mutants. Fld1-∆LR foci colocalize with factors: Nem1, Ldb16, Pex30 and Yft2, which are important for LD biogenesis and these sites become enriched in diacylglycerol upon stimulation of LD formation. Fld1-∆LR forms a homo-oligomeric complex facilitated by protein-protein interactions. We show that mutating the 31st proline abrogates the functioning of Fld1-∆LR. We demonstrate the critical regulatory role of LR of seipin in partitioning triacylglycerol into LDs. We conclude that LR of seipin is dispensable for establishing functional ER sites to recruit proteins for LD biogenesis.

Suggested Citation

  • Amit Khatri & Ritika Chaudhary & R. Mankamna Kumari & Vineet Choudhary, 2025. "The luminal domain region of Seipin/Fld1 is dispensable for establishing functional ER sites for lipid droplet biogenesis," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65645-8
    DOI: 10.1038/s41467-025-65645-8
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