Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

Abstract

Lipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two inter-related mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD-peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1 and CHMP1B modifying LD membrane morphology. Furthermore, M1 Spastin, IST1 and CHMP1B are all required to relieve LDs of lipid peroxidation. M1 Spastin's dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-III components to LD-peroxisome contact sites for FA trafficking may help explain the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.

Membrane constriction and thinning by sequential ESCRT-III polymerization

“…The lumenal cavity of the copolymer was strongly positively charged and capable of shaping negatively charged membranes into positive-curvature membrane tubes in vitro and in vivo. Consistently, studies in living cells have shown that CHMP1B and IST1 co-localize with the VPS4 family member SPASTIN along the positive curvature surfaces of endosomal tubules and contact sites between lipid droplets and peroxisomes ( 10, 14, 15, 26 ). To better understand these new properties and roles for CHMP1B and IST1, and the still unknown structural mechanism by which any ESCRT-III protein interacts with lipid bilayers, we sought to understand how CHMP1B and IST1 work together to bind and constrict membranes.…”

“…First discovered for their role in the formation of multivesicular bodies (MVBs), ESCRT proteins serve essential functions in an expanding range of cellular processes. Beyond MVBs, these processes include: cytokinetic abscission; egress of enveloped viruses; sealing holes in nuclear, endosomal, and plasma membranes ( 1–9 ); and in peroxisome biogenesis and function ( 10, 11 ). ESCRT-III proteins primarily shape negatively-curved membranes, such as the necks of budding viruses or intralumenal vesicles, but we and others have shown that some ESCRT-III proteins can also stabilize positively-curved membranes ( 12–15 ).…”

Maintaining social contacts: The physiological relevance of organelle interactions

“…Since lipid droplets are bounded by a phospholipid monolayer studded with cytosol-exposed proteins, tether proteins on juxtaposed organelles could either bind directly to the lipid droplet membrane via lipid-interacting domains (for example, the ER resident protein DGAT2, which binds the lipid droplet bilayer directly via its C-terminal domain), or via protein-protein interactions between the apposed membranes [ 26 ]. Information about the molecular identities of lipid droplet-peroxisome tethers is scarce, with the protein-protein interaction between the lipid droplet membrane-bound AAA ATPase M1 Spastin and the peroxisomal fatty acid transporter ABCD1 being the best characterised [ 178 ] ( Table 1 ; Fig. 2 ).…”

“…Moreover, M1 Spastin recruits ESCRT III proteins to remodel the lipid droplet membrane, facilitating fatty acid trafficking at these MCSs [ 178 ]. Interestingly, cumyl-OOH treatment, which induces lipid peroxidation and consequently oxidative stress, leads to an increase in the ABCD1-mediated contacts between lipid droplets and peroxisomes which might suggest an additional role of this peroxisome-lipid droplet MCS in redox homeostasis [ 178 ] ( Table 1 ; Fig. 2 ).…”

Spastin mutations impair coordination between lipid droplet dispersion and reticulum

“…Beyond the biogenesis process, mature LDs remain in contact with the ER [19,20], allowing the transfer of lipids and proteins [21]. Contact sites with mitochondria [22,23] and peroxisomes [24] enhance fatty acid exchanges and modulate metabolic functions. These inter-organellar interactions suggest the existence of a finely tuned trafficking.…”