title: Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation.
abstract: The endoplasmic reticulum (ER) mediates the folding, maturation, and deployment of the secretory proteome. Proteins that fail to achieve their native conformation are retained in the ER and targeted for clearance by ER-associated degradation (ERAD), a sophisticated process that mediates the ubiquitin-dependent delivery of substrates to the 26S proteasome for proteolysis. Recent findings indicate that inhibition of long-chain acyl-CoA synthetases with triacsin C, a fatty acid analogue, impairs lipid droplet (LD) biogenesis and ERAD, suggesting a role for LDs in ERAD. However, whether LDs are involved in the ERAD process remains an outstanding question. Using chemical and genetic approaches to disrupt diacylglycerol acyltransferase (DGAT)-dependent LD biogenesis, we provide evidence that LDs are dispensable for ERAD in mammalian cells. Instead, our results suggest that triacsin C causes global alterations in the cellular lipid landscape that disrupt ER proteostasis by interfering with the glycan trimming and dislocation steps of ERAD. Prolonged triacsin C treatment activates both the IRE1 and PERK branches of the unfolded protein response and ultimately leads to IRE1-dependent cell death. These findings identify an intimate relationship between fatty acid metabolism and ER proteostasis that influences cell viability.
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Milton
authors.initials: M
authors.lastname: To
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Clark W H
authors.initials: CW
authors.lastname: Peterson
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Roberts
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.|Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720.|Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Counihan
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Wu
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Mercedes S
authors.initials: MS
authors.lastname: Forster
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720.|Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720.|Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720 olzmann@berkeley.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Olzmann
mesh_terms: D000818:Animals; D002460:Cell Line; D051048:Diacylglycerol O-Acyltransferase; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000502:physiology; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology; D006801:Humans; D066292:Lipid Droplets / Q000502:physiology*; D008055:Lipids / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D059748:Proteolysis; D014226:Triazenes; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology
chemical_list: D008055:Lipids; D008565:Membrane Proteins; D011134:Polysaccharides; D014226:Triazenes; D025801:Ubiquitin; C034613:triacsin C; D051048:Diacylglycerol O-Acyltransferase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease