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.

Keywords: ERAD; cholesterol; lipid droplet; quality control; triacylglycerol; ubiquitin.

Figure 1

Mechanisms of protein quality and quantity control in the endoplasmic reticulum (ER). (a) Protein folding and maturation in the ER. Proteins inserted through the Sec61 translocon are subject to cotranslational and posttranslational folding. Proteins that have achieved their native conformation are recognized and transported to their final cellular destination. Proteins failing to achieve their proper conformation are triaged for ER-associated degradation (ERAD) (quality control). The levels of some properly folded proteins are also controlled by regulated degradation by ERAD (quantity control). (b) ERAD mediates the delivery of proteins from the ER to the cytosolic 26S proteasome through a series of coupled steps: ① substrate recognition, ② dislocation and ubiquitin conjugation, and ③ targeting of the ubiquitinated proteins to the proteasome for ④ proteolysis. (c) The ERAD system comprises multiple pathways that mediate the recognition and degradation of topologically diverse substrates. These pathways are commonly designated based upon the location of the substrate degradation signal: luminal (ERAD-L), cytosolic (ERAD-C), membrane (ERAD-M), or translocon (ERAD-T). (Yellow star indicates degradation signal; orange triangle indicates N-glycan.)

Figure 2

ERAD regulation of cholesterol metabolism. (a) Schematic of the cholesterol synthesis pathway with the points of ERAD-mediated regulation indicated. Regulated enzymes are shown in blue boxes and ERAD machinery in red boxes. (b) In the presence of sterols, Insigs recruit HMGCR to the gp78 and Trc8 complexes for degradation. For simplicity, only gp78 is illustrated. Sterols also stimulate the interaction of HMGCR with UBIAD1, which impairs the dislocation of a portion of HMGCR. Geranylgeranyl-PP binding releases UBIAD1 from the degradation complex, promoting HMGCR dislocation and degradation. The released UBIAD1 traffics to the Golgi complex. (c) Cholesterol induces MARCH6 degradation of squalene monooxygenase, whereas unsaturated FAs stabilize it. Abbreviations: ERAD, endoplasmic reticulum-associated degradation; FA, fatty acid; uFA, unsaturated fatty acid; gp78, glycoprotein 78; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Insig, insulin-induced gene protein; MARCH6, membrane-associated RING finger protein 6; PP, pyrophosphate; Trc8, translocation in renal carcinoma on chromosome 8 protein; UBIAD1, UbiA prenyltransferase domain–containing protein 1.

Figure 3

ERAD regulation of triacylglycerol metabolism. (a) Schematic of the triacylglycerol synthesis and degradation pathways with the points of ERAD-mediated regulation indicated. Regulated enzymes are shown in blue boxes and ERAD machinery in red boxes. (b) Constitutive DGAT2 degradation is mediated by gp78. Under low FA conditions, UBXD8 inhibits TAG synthesis. Increases in FA levels release UBXD8 inhibition of TAG synthesis and promote UBXD8 trafficking to LDs. On LDs, UBXD8 impairs lipolysis through the dissociation of ATGL from its cofactor CGI-58. Abbreviations: ATGL, adipose triglyceride lipase; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; ERAD, endoplasmic reticulum-associated degradation; FA, fatty acid; uFA, unsaturated fatty acid; FA-CoA, fatty acid coenzyme A; gp78, glycoprotein 78; LD, lipid droplet; TAG, triacylglycerol; UBAC2, UBA domain–containing protein 2; UBXD8, UBX domain–containing protein 8; VCP, valosin-containing protein.

Figure 4

ER-associated degradation control of master transcriptional regulators of lipid metabolism. In the presence of sterols, Insigs mediate the ER retention of the SCAP-SREBP complex. In the absence of sterols, a gp78-UBXD8 complex degrades Insigs, and SCAP-SREBP traffics to the Golgi complex. In the Golgi complex, SREBP is proteolytically processed at two sites, releasing a soluble transcription factor that binds SRE sequences and induces expression of lipid-related genes. Abbreviations: ER, endoplasmic reticulum; gp78, glycoprotein 78; Insig, insulin-induced gene; SCAP, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBP, sterol regulatory element–binding protein; UBXD8, UBX domain–containing protein 8; VCP, valosin-containing protein.