Journal
EMBO JOURNAL
Volume 35, Issue 24, Pages 2699-2716Publisher
WILEY-BLACKWELL
DOI: 10.15252/embj.201695170
Keywords
electron microscopy; lipid storage; lipodystrophy; membrane contact sites
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Funding
- Academy of Finland [272130, 282192, 284667, 131650, 1287975]
- Finnish Medical Foundation
- Helsinki Biomedical Graduate School
- Sigrid Juselius Foundation
- Biocenter Finland
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- Aide aux Jeunes Diabetiques
- Societe Francophone du Diabete
- Deutsche Forschungsgemeinschaft [SFB645]
- Biomedicum Imaging Unit
- Academy of Finland (AKA) [272130, 284667, 131650, 284667, 272130, 131650] Funding Source: Academy of Finland (AKA)
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Seipin is an endoplasmic reticulum (ER) membrane protein implicated in lipid droplet (LD) biogenesis and mutated in severe congenital lipodystrophy (BSCL2). Here, we show that seipin is stably associated with nascent ER-LD contacts in human cells, typically via one mobile focal point per LD. Seipin appears critical for such contacts since ER-LD contacts were completely missing or morphologically aberrant in seipin knockout and BSCL2 patient cells. In parallel, LD mobility was increased and protein delivery from the ER to LDs to promote LD growth was decreased. Moreover, while growing LDs normally acquire lipid and protein constituents from the ER, this process was compromised in seipin-deficient cells. In the absence of seipin, the initial synthesis of neutral lipids from exogenous fatty acid was normal, but fatty acid incorporation into neutral lipids in cells with pre-existing LDs was impaired. Together, our data suggest that seipin helps to connect newly formed LDs to the ER and that by stabilizing ER-LD contacts seipin facilitates the incorporation of protein and lipid cargo into growing LDs in human cells.
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