Seipin regulates ER–lipid droplet contacts and cargo delivery

Abstract

Seipin is an endoplasmic reticulum (ER) membrane protein implicated in lipid droplet (LD) biogenesis and mutated in severe congenital lipodystrophy (BSCL2). Here, we show that seipin is stably associated with nascent ER–LD contacts in human cells, typically via one mobile focal point per LD. Seipin appears critical for such contacts since ER–LD contacts were completely missing or morphologically aberrant in seipin knockout and BSCL2 patient cells. In parallel, LD mobility was increased and protein delivery from the ER to LDs to promote LD growth was decreased. Moreover, while growing LDs normally acquire lipid and protein constituents from the ER, this process was compromised in seipin‐deficient cells. In the absence of seipin, the initial synthesis of neutral lipids from exogenous fatty acid was normal, but fatty acid incorporation into neutral lipids in cells with pre‐existing LDs was impaired. Together, our data suggest that seipin helps to connect newly formed LDs to the ER and that by stabilizing ER–LD contacts seipin facilitates the incorporation of protein and lipid cargo into growing LDs in human cells.

Establishing the lipid droplet proteome: Mechanisms of lipid droplet protein targeting and degradation

“…The protein composition of LD-enriched buoyant fractions isolated from many species and cell types has been extensively analyzed by proteomics [19–39]. However, this method yields many false positives due to contamination of buoyant fractions with co-fractionating organelles or membrane remnants, which likely reflects physical associations of LDs with the ER [40–44], mitochondria [7,8,45], peroxisomes [46,47], and early endosomes [48]. Indeed, abundant ER proteins (e.g.…”

“…At the junction of other organelles connected by contiguous membranes there are often proteins that regulate the diffusion barriers to maintain the correct proteomes, such as septin 2 at the junction between the plasma membrane and primary cilium [102] and the nuclear pore complex at the junction between the inner and outer nuclear membranes [103]. Seipin is positioned at ER-LD contact sites [41,42,44,104], but whether seipin or another protein acts as a “gatekeeper” to control protein diffusion between the ER and LDs is unknown.…”

The collaborative work of droplet assembly

“…The supersized droplets are suppressed in cells cultured in high inositol, a condition that stimulates phospholipid synthesis. Multiple small droplets are also seen in fibroblasts from BSCL2 patients [2, 42]. The droplets generated in the absence of seipin are not fully functional.…”

Mitochondrial junctions with cellular organelles: Ca2+ signalling perspective

“…Another protein seipin was recently shown to be important for the ER-LD contacts as well as being involved in lipid and protein delivery from ER to LD [144]. …”