Spartin-mediated lipid transfer facilitates lipid droplet turnover

Abstract

Lipid droplets (LDs) are organelles critical for energy storage and membrane lipid homeostasis, whose number and size are carefully regulated in response to cellular conditions. The molecular mechanisms underlying lipid droplet biogenesis and degradation, however, are not well understood. The Troyer syndrome protein spartin (SPG20) supports LD delivery to autophagosomes for turnover via lipophagy. Here, we characterize spartin as a lipid transfer protein whose transfer ability is required for LD degradation. Spartin co-purifies with phospholipids and neutral lipids from cells and transfers phospholipids in vitro via its senescence domain. A senescence domain truncation that impairs lipid transfer in vitro also impairs LD turnover in cells while not affecting spartin association with either LDs or autophagosomes, supporting that spartin’s lipid transfer ability is physiologically relevant. Our data indicate a role for spartin-mediated lipid transfer in LD turnover.SignificanceThe Troyer syndrome protein spartin was proposed to function as a lipophagy receptor that delivers lipid droplets, organelles key for energy storage and membrane lipid homeostasis, to autophagosomes for degradation. We identify an additional function for spartin as a lipid transfer protein and show its transfer ability is required for lipid droplet degradation, including by lipophagy. Our data support that protein-mediated lipid transfer plays a role in lipid droplet turnover. Moreover, in spartin’s senescence domain we have discovered a new lipid transport module that likely also features in still undiscovered aspects of lipid droplet biology and membrane homeostasis.

Emerging functions of the mitochondria–ER–lipid droplet three‐way junction in coordinating lipid transfer, metabolism, and storage in cells

“…Recently, the protein spartin, found to localize to both LD and endosomal compartment and to act as lipophagy receptor [79], has been shown to have the ability to transfer phospholipids via its senescence domain [80], and it links LD to autophagy machinery to mediate lipophagy [79]. Interestingly, Wan et al revealed that the role of spartin in LD turnover is dependent on its senescence domain, and therefore, it may require spartin lipid transfer activity [80]. However, whether this process happens at ERmitochondria-LD contacts remains to be elucidated.…”

“…Recently, the protein spartin, found to localize to both LD and endosomal compartment and to act as lipophagy receptor [79], has been shown to have the ability to transfer phospholipids via its senescence domain [80], and it links LD to autophagy machinery to mediate lipophagy [79]. Interestingly, Wan et al .…”

“…Interestingly, Wan et al . revealed that the role of spartin in LD turnover is dependent on its senescence domain, and therefore, it may require spartin lipid transfer activity [80]. However, whether this process happens at ER–mitochondria–LD contacts remains to be elucidated.…”