Born this way – Biogenesis of lipid droplets from specialized ER subdomains

Highlights

• Lipid droplets (LDs) are generated from specialized regions of the ER.

• ER proteins seipin, Pex30 and FIT2 act as LD biogenesis factors.

• LD formation likely depends on a locally optimized membrane environment.

• Nutrient stress results in local LD biogenesis at the nucleus-vacuole contact site.

Abstract

Both the endoplasmic reticulum (ER) and lipid droplets (LDs) are key players in lipid handling. In addition to this functional connection, the two organelles are also tightly linked due to the fact that the ER is the birthplace of LDs. LDs have an atypical architecture, consisting of a neutral lipid core that is covered by a phospholipid monolayer. LD biogenesis starts with neutral lipid synthesis in the ER membrane and formation of small neutral lipid lenses between its leaflets, followed by budding of mature LDs toward the cytosol.

Several ER proteins have been identified that are required for efficient LD formation, among them seipin, Pex30, and FIT2. Recent evidence indicates that these LD biogenesis factors might cooperate with specific lipids, thus generating ER subdomains optimized for LD assembly. Intriguingly, LD biogenesis reacts dynamically to nutrient stress, resulting in a spatial reorganization of LD formation in the ER.

Introduction

The endoplasmic reticulum (ER) has a central role in lipid handling. It houses numerous enzymes involved in generation of both neutral storage lipids (triacylglycerols/TAGs and sterol esters), and polar membrane lipids such as phospholipids, sterols, and sphingolipids. A second cellular key player in the handling of lipids is the lipid droplet (LD). LDs are ubiquitous organelles specialized in neutral lipid storage, which additionally participate in neutral lipid biogenesis and breakdown as well as in phospholipid and sterol synthesis. ER and LDs have an intimate connection not only with respect to their overlapping functions, but also because biogenesis of LDs takes place within the ER membrane.

Unlike most organelles, which typically consist of a central aqueous compartment bordered by a phospholipid bilayer, LDs are composed of a neutral lipid core surrounded by a phospholipid monolayer. The exact mechanism by which these unique structures are formed is still under debate, but the prevailing model for LD biogenesis suggests the following steps (Fig. 1; reviewed in detail in [1]): First, neutral lipids are synthesized within the ER membrane. Second, oil lenses form between the leaflets of the ER membrane through lipid demixing. Structures with a topology equivalent to oil lenses have been observed in cultured hepatocytes, where binding of lipidated apolipoprotein B-100 stabilizes an intermediate of LD formation [2], and nascent lens-like LDs were also observed in a yeast model system for de novo LD biogenesis [3]. Third, neutral lipid structures covered by the cytosolic leaflet of the ER membrane bud toward the cytosol. In yeast, mature LDs appear to stay connected with the ER membrane via lipidic stalk structures throughout their lifetime [[4], [5], [6], [7]], while in higher eukaryotes, LDs have been reported to either remain in physical contact with the ER or alternatively be completely released [[8], [9], [10]].

Biogenesis of LDs depends on supply of its different structural components. On one hand, neutral lipid synthesizing enzymes are needed for production of the different types of storage fat that make up the LD core, reviewed in [1]. On the other hand, several protein targeting pathways are required for biogenesis of the LD proteome, which decorates the LD surface and is needed for the metabolic activities of the organelle, reviewed in [11]. Perilipins are a family of abundant LD surface proteins (five members in human, Plin1-5) that have important functions in LD biology. A key role of perilipins is the regulation of LD stability by keeping lipolysis at bay [12]. Human Plin3 and Plin4, and also the yeast perilipin Pln1, have been suggested to be involved in LD biogenesis [[13], [14], [15], [16]].

Recent seminal studies have started to uncover molecular players involved in the mechanistic steps of the LD assembly process. The ER proteins seipin, Pex30, and FIT2 have been identified that mark sites of LD biogenesis, and that are required for efficient LD formation. In this review, we describe the features of these LD biogenesis proteins and highlight recent hypotheses on their mechanistic roles. Initial evidence indicates that these proteins might collaborate with specific lipids, and potentially generate local membrane environments optimized for LD budding. In yeast, the spatial organization of LD biogenesis responds dramatically to conditions of nutrient stress, pointing toward a key regulatory role of ER membrane organization in adaptation to metabolic alterations.