Abstract
Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in cellular metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. During LD biogenesis and growth, this monolayer of lipids expands by acquiring phospholipids from the endoplasmic reticulum (ER) through nonvesicular mechanisms. Here, in a mini-screen, we find that ORP5, an integral membrane protein of the ER, can localize to ER-LD contact sites upon oleate loading. ORP5 interacts with LDs through its ligand-binding domain, and ORP5 deficiency enhances neutral lipid synthesis and increases the size of LDs. Importantly, there is significantly more phosphatidylinositol-4-phosphate (PI(4)P) and less phosphatidylserine (PS) on LDs in ORP5-deficient cells than in normal cells. The increased presence of PI(4)P on LDs in ORP5-deficient cells requires phosphatidylinositol 4-kinase 2-α. Our results thus demonstrate the existence of PI(4)P on LDs and suggest that LD-associated PI(4)P may be primarily used by ORP5 to deliver PS to LDs.
Highlights
Lipid droplets (LDs) are intracellular organelles that are the primary sites for storing excess lipids (Bersuker et al, 2018; Farese and Walther, 2009; Gao et al, 2019; Olzmann and Carvalho, 2019; Yang et al, 2012)
We found that ORP5, a protein implicated in the transfer of PS from the endoplasmic reticulum (ER) to the plasma membrane (PM; Chung et al, 2015; Ghai et al, 2017; Moser von Filseck et al, 2015; Sohn et al, 2018), localized to ER–LD contact sites upon oleate loading
ORP5 localizes to the LD surface To examine the potential role of oxysterol binding protein (OSBP)/ORPs in regulating LD dynamics, we performed a mini-scale localization screen
Summary
Lipid droplets (LDs) are intracellular organelles that are the primary sites for storing excess lipids (Bersuker et al, 2018; Farese and Walther, 2009; Gao et al, 2019; Olzmann and Carvalho, 2019; Yang et al, 2012). The surface of LDs is unique among cellular organelles because of its monolayer nature as opposed to bilayer membranes. A large number of proteins are attached to the surface of LDs, and these LD-associated proteins often play crucial roles in cellular metabolism. The composition of LD surface lipids impacts LD biogenesis and growth (Fei et al, 2011; Gao et al, 2019) and dictates the targeting and function of LD-associated proteins. FSP27 plays a critical role in the formation of unilocular LDs (Gong et al, 2011; Nishino et al, 2008), and the amount of phosphatidic acid on the LD surface was reported to impact FSP27 function in LD growth/fusion (Barneda et al, 2015). The composition of LD surface monolayer is crucial to LD function
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