Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

Abstract

The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol, triacylglycerol, and phospholipids. Protein production within the endoplasmic reticulum is tightly regulated by a cohort of resident machinery that coordinates the folding, modification, and deployment of secreted and integral membrane proteins. Proteins failing to attain their native conformation are degraded through the endoplasmic reticulum–associated degradation (ERAD) pathway via a series of tightly coupled steps: substrate recognition, dislocation, and ubiquitin-dependent proteasomal destruction. The same ERAD machinery also controls the flux through various metabolic pathways by coupling the turnover of metabolic enzymes to the levels of key metabolites. We review the current understanding and biological significance of ERAD-mediated regulation of lipid metabolism in mammalian cells.

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

“…Consistent with this possibility, a recent study in yeast demonstrated that hairpin motifs were sufficient to target proteins for degradation through ERAD [106]. ERAD enables the cytosolic degradation of proteins from the early secretory pathway by mediating their recognition, ubiquitination, and subsequent extraction from the ER membrane by the AAA ATPase VCP (Cdc48 in yeast) [109–111]. Deletion of the yeast, polytopic ERAD E3 ligase Doa10p or its cognate E2 ubiquitin-conjugating enzymes Ubc6p or Ubc7p stabilized the Class I LD protein Pgc1p in the ER [106].…”

“…Organelles contain specialized pathways (e.g. ER-associated degradation [ERAD] [109–111]) that mediate the recognition of their respective proteomes for degradation. These include quality control pathways that degrade misfolded and damaged proteins (e.g.…”

“…mutant proteins involved in human diseases) as well as quantity control pathways that degrade correctly folded, functional proteins in order to regulate cellular processes (e.g. metabolic enzymes such as HMG-CoA Reductase in cholesterol biosynthesis) [109–111]. Covalent modification of substrate proteins with a polyubiquitin chain is the canonical signal that targets substrates to the 26S proteasome for proteolytic degradation [112].…”

New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation

“…Moreover, nearly 70 human diseases have been linked to ERAD (2). While the biochemical processes of ERAD have been well characterized in the last two decades (8-10), the physiological significance of mammalian ERAD at the organismal level remains vague. This is an especially challenging problem given a vast number of different cell types and their crosstalk in mammals.…”

Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation

“…To ensure the fidelity of the secretory proteome, the ER has evolved a quality control system that detects terminally misfolded and unoligomerized proteins and targets them for clearance via a process known as ER-associated degradation (ERAD; Olzmann et al. , 2013a; Christianson and Ye, 2014; Stevenson et al. , 2016).…”