Identification of two pathways mediating protein targeting from ER to lipid droplets

Abstract

Pathways localizing proteins to their sites of action are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, how proteins, such as metabolic enzymes, target from the endoplasmic reticulum (ER) to cellular lipid droplets (LDs) is poorly understood. Here we identify two distinct pathways for ER-to-LD protein targeting: early targeting at LD formation sites during formation, and late targeting to mature LDs after their formation. Using systematic, unbiased approaches in Drosophila cells, we identified specific membrane-fusion machinery, including regulators, a tether and SNARE proteins, that are required for the late targeting pathway. Components of this fusion machinery localize to LD–ER interfaces and organize at ER exit sites. We identified multiple cargoes for early and late ER-to-LD targeting pathways. Our findings provide a model for how proteins target to LDs from the ER either during LD formation or by protein-catalysed formation of membrane bridges.

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size

“…After avoiding translocation, APOE traffics to LDs from the cytoplasmic surface of the ER via membrane bridges. Recent study of the mechanism of protein trafficking from the ER to LDs identified both "early" and "late" ER to LD (ERTOLD) pathways (Song et al, 2022). Given that we observe APOE coating LDs several hours into OA treatment, we hypothesize that it may move onto LDs via the "late" pathway.…”

Designing Intracellular Compartments for Efficient Engineered Microbial Cell Factories

“…These ER-LD connections facilitate the exchange of proteins and lipids between the two compartments. It is believed that this transport occurs through membrane continuity, so the dual location strategy of LDs and ER may be a more effective choice when using compartmentalization strategies to increase metabolite flux (Figure b,c). Guo et al divided the ER-located enzymes in the 7-dehydrocholesterol (7-DHC) synthetic pathway into four modules and then targeted modules ERG25/26/27 and ERG2/3 into LDs to promote the conversion efficiency of sterol intermediates to 7-DHC by using the dual localization of ER and LDs …”

Bioorthogonal Imaging Uncovers Sex- and Diet-dependent Lipid Metabolic Changes in Drosophila Brain during Aging

“…However, we have not examined the lipid exchange between the cell membrane and LDs due to technical obstacles. A recent genome wide RNA interference (RNAi) screen using Drosophila cells has identi ed multiple players in targeting proteins from the endoplasmic reticulum to LDs, both during the early phase at LD formation sites and late stage targeting to mature LDs (Song et al, 2022). Further study is necessary to fully understand mechanisms controlling LD metabolism.…”