Spartin is a Lipid Transfer Protein That Facilitates Lipid Droplet Turnover

Abstract

One means by which cells reutilize neutral lipids stored in lipid droplets is to degrade them by autophagy. This process involves spartin, mutations of which cause the rare inherited disorder Troyer syndrome (or spastic paraplegia-20, SPG20). A recently published paper from the team led by Karin Reinsich (Yale) suggests that the molecular function of spartin and its unique highly conserved "senescence" domain is as a lipid transfer protein. Spartin binds to and transfers all lipid species found in lipid droplets, from phospholipids to triglycerides and sterol esters. This lipid transfer activity correlates with spartin's ability to sustain lipid droplet turnover. The senescence domain poses an intriguing question around the wide range of its cargoes, but intriguingly it has yet to yield up its secrets because attempts at crystallization failed and AlphaFold's prediction is unconvincing.

Keywords: autophagy; lipophagy; lysophagy; membrane contact sites; spastin.

Figure 1.

Domain diagram of Spartin protein and model of its interaction with autophagosomes and lipid droplets. (A) Three domains and two motifs in human spartin are shown with their boundaries. (B) The N-terminal LC3A/C-interacting region (LIR) motif targets LC3 on autophagosomes. (C) The C-terminal senescence domain, which interacts with the lipid monolayer of lipid droplets, consists of four amphipathic helices (H1–4) that are capable of solubilizing both polar and neutral lipids. While both pairs of helices H1/2 and H3/4 are required for lipid transfer by spartin, only H1/2 affects its localization to LDs.