Cargando…

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

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 ubiquiti...

Descripción completa

Detalles Bibliográficos
Autores principales: To, Milton, Peterson, Clark W. H., Roberts, Melissa A., Counihan, Jessica L., Wu, Tiffany T., Forster, Mercedes S., Nomura, Daniel K., Olzmann, James A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231896/
https://www.ncbi.nlm.nih.gov/pubmed/27881664
http://dx.doi.org/10.1091/mbc.E16-07-0483
_version_ 1782494576015048704
author To, Milton
Peterson, Clark W. H.
Roberts, Melissa A.
Counihan, Jessica L.
Wu, Tiffany T.
Forster, Mercedes S.
Nomura, Daniel K.
Olzmann, James A.
author_facet To, Milton
Peterson, Clark W. H.
Roberts, Melissa A.
Counihan, Jessica L.
Wu, Tiffany T.
Forster, Mercedes S.
Nomura, Daniel K.
Olzmann, James A.
author_sort To, Milton
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5231896
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-52318962017-03-30 Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation To, Milton Peterson, Clark W. H. Roberts, Melissa A. Counihan, Jessica L. Wu, Tiffany T. Forster, Mercedes S. Nomura, Daniel K. Olzmann, James A. Mol Biol Cell Articles 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. The American Society for Cell Biology 2017-01-15 /pmc/articles/PMC5231896/ /pubmed/27881664 http://dx.doi.org/10.1091/mbc.E16-07-0483 Text en © 2017 To, Peterson, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
To, Milton
Peterson, Clark W. H.
Roberts, Melissa A.
Counihan, Jessica L.
Wu, Tiffany T.
Forster, Mercedes S.
Nomura, Daniel K.
Olzmann, James A.
Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation
title Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation
title_full Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation
title_fullStr Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation
title_full_unstemmed Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation
title_short Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation
title_sort lipid disequilibrium disrupts er proteostasis by impairing erad substrate glycan trimming and dislocation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231896/
https://www.ncbi.nlm.nih.gov/pubmed/27881664
http://dx.doi.org/10.1091/mbc.E16-07-0483
work_keys_str_mv AT tomilton lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation
AT petersonclarkwh lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation
AT robertsmelissaa lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation
AT counihanjessical lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation
AT wutiffanyt lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation
AT forstermercedess lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation
AT nomuradanielk lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation
AT olzmannjamesa lipiddisequilibriumdisruptserproteostasisbyimpairingeradsubstrateglycantrimminganddislocation