Seipin and perilipin 3 promote distinct early steps of nascent lipid droplet biogenesis
Abstract
Lipid droplets (LDs) are lipid storage organelles with critical roles in metabolism. Cells form LDs in response to various metabolic stresses (1). LD biogenesis occurs in the endoplasmic reticulum (ER) membrane and begins when triglyceride (TG) in the membrane phase separates (2-4). After nucleation, nascent LDs grow by absorbing TG from the membrane (5,6). How cells determine when TG in the ER membrane is added to existing LDs or is used to form new LDs or is not known. Here, we developed the first LD formation assay that allows the synthesis of TG in membranes, mimicking what occurs in cells. LDs arise stochastically after TG production begins. LD nucleation is affected by TG production rate and membrane phospholipid composition. Membrane-embedded LDs suppress nascent LD formation by sequestering TG and destabilizing nascent LDs by Ostwald ripening. We show that cells overcome this suppression in two ways. The ER membrane protein seipin accelerates LD nucleation where it localizes in a membrane, probably by increasing the kinetics of TG phase separation. The LD coat perilipin 3 inhibits nascent droplet dissipation by ripening. Together, our findings reveal a minimal LD formation machinery, and the mechanisms cells use to control whether TG in the ER drives new LD formation.
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BibTeX
@misc{deo2026seipin,
title = {{Seipin and perilipin 3 promote distinct early steps of nascent lipid droplet biogenesis}},
author = {Raunaq Deo and Apoorva Bhapkar and Emma Givan and Chao Li and Ehud Haimov and Derk Binns and Philipp E Scherer and Michael M. Kozlov and Alexandre Toulmay and William A. Prinz},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.760741},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760741v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Seipin and perilipin 3 promote distinct early steps of nascent lipid droplet biogenesis
AU - Raunaq Deo
AU - Apoorva Bhapkar
AU - Emma Givan
AU - Chao Li
AU - Ehud Haimov
AU - Derk Binns
AU - Philipp E Scherer
AU - Michael M. Kozlov
AU - Alexandre Toulmay
AU - William A. Prinz
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.760741
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.760741v1
AB - Lipid droplets (LDs) are lipid storage organelles with critical roles in metabolism. Cells form LDs in response to various metabolic stresses (1). LD biogenesis occurs in the endoplasmic reticulum (ER) membrane and begins when triglyceride (TG) in the membrane phase separates (2-4). After nucleation, nascent LDs grow by absorbing TG from the membrane (5,6). How cells determine when TG in the ER membrane is added to existing LDs or is used to form new LDs or is not known. Here, we developed the first LD formation assay that allows the synthesis of TG in membranes, mimicking what occurs in cells. LDs arise stochastically after TG production begins. LD nucleation is affected by TG production rate and membrane phospholipid composition. Membrane-embedded LDs suppress nascent LD formation by sequestering TG and destabilizing nascent LDs by Ostwald ripening. We show that cells overcome this suppression in two ways. The ER membrane protein seipin accelerates LD nucleation where it localizes in a membrane, probably by increasing the kinetics of TG phase separation. The LD coat perilipin 3 inhibits nascent droplet dissipation by ripening. Together, our findings reveal a minimal LD formation machinery, and the mechanisms cells use to control whether TG in the ER drives new LD formation.
SN - 2692-8205
ER -