Lipids and their (un)known effects on ER-associated protein degradation (ERAD)

Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a conserved cellular process that apart from protein quality control and maintenance of ER membrane identity has pivotal functions in regulating the lipid composition of the ER membrane. A general trigger for ERAD activation is the exposure of normally buried protein domains due to protein misfolding, absence of binding partners or conformational changes. Several feedback loops for ER lipid homeostasis exploit the induction of conformational changes in key enzymes of lipid biosynthesis or in ER membrane-embedded transcription factors upon shortage or abundance of specific lipids, leading to enzyme degradation or mobilization of transcription factors. Similarly, an insufficient amount of lipids triggers ERAD of apolipoproteins during lipoprotein formation. Lipids might even have a role in ER protein quality control: when proteins destined for ER export are covalently modified with lipids their ER residence time and their susceptibility to ERAD is reduced. Here we summarize and compare the various interconnections of lipids with ER membrane proteins and ERAD. This article is part of a Special Issue entitled Endoplasmic reticulum platforms for lipid dynamics edited by Shamshad Cockcroft and Christopher Stefan.