Seipin collaborates with the ER membrane to control the sites of lipid droplet formation

Abstract

Most cells store metabolic energy in lipid droplets (LDs). LDs are composed of a hydrophobic core, covered by a phospholipid monolayer, and functionalized by a specific set of proteins. Formation of LDs takes place in the endoplasmic reticulum (ER), where neutral lipid biosynthetic enzymes are located. Recent evidence indicate that this process is confined to specific ER subdomains, where proteins meet to initiate LD assembly. The lipodystrophy protein Seipin, is emerging as a major coordinator of LD biogenesis. Seipin forms a large oligomeric toroidal structure, which traps neutral lipids to promote LD nucleation. Here, we discuss the role of LD biogenesis factors that associate with Seipin to assemble functional LDs.

Figure 1. Lipin activity controls membrane expansion and storage lipid synthesis.

The activity of the phosphatidate phosphatase, Lipin (Pah1), which promotes hydrolysis of phosphatidic acid (PA) to diacylglycerol (DAG), is controlled by the ER localized phosphatase complex Nem1/Spo7. While PA acts as precursor for the synthesis of abundant phospholipids and hence for membrane expansion, DAG acts as substrate for production of the storage lipid TAG by acyltransferases, such as DGAT/Dga1, and thus induces LD biogenesis.

Figure 2. The ordered formation of LDs at discrete sites in the ER membrane.

a) LD biogenesis occurs at discrete ER domains. Fluorescence microscopy image of a yeast strain expressing mCherry-tagged Seipin, induced to form TAG, which drives de novo formation of LDs. Scale bar, 5 μm. b, c) Schematic view of interactions between components needed for LD formation. Seipin is required at the center to promote NL nucleation within the ER membrane. Seipin is assisted by LD factors such as Pex30, and LDAF1/Promethin (see Table 1), and controls the production of PA. The Nem1/Spo7 complex activates Lipin to promote DAG formation, which then serves as substrate for TAG synthesis by DGAT enzymes. Nem1/Spo7 activity is inhibited by Ice2. Upon LD growth and maturation, LD proteins including perilipins (PLIN) localize onto the limiting monolayer. DAG in the ER membrane is depicted by red circles and TAG by the yellow sphere. d) Model of the oligomeric structure of human Seipin. NL nucleation is promoted by the membrane apposed hydrophobic helix (red) within the luminal domain of the Seipin inner ring. The two transmembrane domains of Seipin are not shown.