The CYTOLD and ERTOLD pathways for lipid droplet–protein targeting

Lipid droplet (LD) organelles contain specific proteins, including metabolic enzymes, that differ among cell types. Proteins targeting the monolayer surface of lipid droplets do not follow the same principles as proteins targeting bilayer membranes. The targeting of proteins to lipid droplet surfaces is governed by the biophysical features of their unique oil–water interface. LD protein targeting occurs via two major pathways: CYTOLD and ERTOLD targeting. Elucidating the principles driving these protein targeting pathways has implications for further understanding physiology and metabolic diseases. Lipid droplets (LDs) are the main organelles for lipid storage, and their surfaces contain unique proteins with diverse functions, including those that facilitate the deposition and mobilization of LD lipids. Among organelles, LDs have an unusual structure with an organic, hydrophobic oil phase covered by a phospholipid monolayer. The unique properties of LD monolayer surfaces require proteins to localize to LDs by distinct mechanisms. Here we review the two pathways known to mediate direct LD protein localization: the CYTOLD pathway mediates protein targeting from the cytosol to LDs, and the ERTOLD pathway functions in protein targeting from the endoplasmic reticulum to LDs. We describe the emerging principles for each targeting pathway in animal cells and highlight open questions in the field. Lipid droplets (LDs) are the main organelles for lipid storage, and their surfaces contain unique proteins with diverse functions, including those that facilitate the deposition and mobilization of LD lipids. Among organelles, LDs have an unusual structure with an organic, hydrophobic oil phase covered by a phospholipid monolayer. The unique properties of LD monolayer surfaces require proteins to localize to LDs by distinct mechanisms. Here we review the two pathways known to mediate direct LD protein localization: the CYTOLD pathway mediates protein targeting from the cytosol to LDs, and the ERTOLD pathway functions in protein targeting from the endoplasmic reticulum to LDs. We describe the emerging principles for each targeting pathway in animal cells and highlight open questions in the field. membrane lipid that corresponds to isoprenoid polymers, also known as ‘polyisoprenoid alcohols’, which synthesized on the cytosolic side of the ER membrane and exist as a mixture of species of different chain lengths. During N-linked protein glycosylation, they function as lipid carriers of the glycan molecules destined to be conjugated to proteins. protein complexes of ~600 kDa that form in the ER membrane by oligomers of seipin and accessory proteins such as LDAF1 (Ldb16 and Ldo protein in yeast). LDACs define the sites of LD formation in the ER membrane and are thought to promote the nucleation and phase separation of TG lenses. lipids covalently attached to proteins and also integrated into membranes, allowing the stable interaction of proteins with membranes. There are three main types of lipid anchors: isoprene polymers (e.g., farnesyl, geranylgeranyl), FAs (e.g., saturated myristic acid and palmitic acid), and glycosylphosphatidylinositol (GPI). conditions in which patients are unable to produce and maintain healthy fat tissue, resulting in metabolic complications (e.g., fatty liver, insulin resistance). They are caused by preventing the differentiation, survival, or functionality of adipocytes. Lipodystrophies can be classified on the basis of their origin (i.e., congenital versus acquired) or the extent to which the fat tissue is compromised (i.e., generalized versus partial). the catabolism or degradation of the TGs stored in LDs. It occurs in three sequential steps, mediated by the enzymes ATGL, HSL, and monoglyceride lipase (MGL), and produces FAs and glycerol. liver condition characterized by the excessive accumulation of fat in the liver (i.e., hepatic steatosis) that is caused by metabolic disease, often with insulin resistance, rather than excessive alcohol intake, medication, or hereditary disorders. Specifically, it is defined by the accumulation of large and heterogeneously sized LDs, consisting mainly of TGs, in >5% of hepatocytes. condition that results from the progression of NAFLD to more serious conditions, such as hepatocyte inflammation and liver tissue fibrosis. Chronic liver fibrosis and damage can lead to cirrhosis and liver failure. proteins of ~15–26 kDa that are characteristic of LDs from plant cells, particularly of seed LDs. They play a structural role since they coat the surface of LDs, providing stability and preventing them from coalescing with other LDs. Oleosins contain a long, hydrophobic hairpin motif (72 amino acids) that is involved in its targeting to LDs from the ER. protein encoded by the Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) gene, which can harbor mutations causing lipodystrophy. It forms oligomers in the ER membrane, and it is involved in defining the sites of LD formation (as part of the LDAC) and in stabilizing the ER–LD connections.