Misfolded proteins in the endoplasmic reticulum (ER) are removed through a process known as endoplasmic reticulum associated degradation (ERAD). ERAD occurs through an integral membrane protein quality control system that recognizes substrates, retrotranslocates the substrates across the membrane, ubiquitinates and extracts the substrates from the membrane for degradation at the cytosolic proteasome. While ERAD systems are known to regulate lipid biosynthetic enzymes, the regulation of ERAD systems by the lipid composition of cellular membranes remains unexplored. Here, we report that the ER membrane composition controls ERAD function by incapacitating substrate extraction. Unbiased lipidomic profiling revealed that elevation of specific very-long chain ceramides leads to a dramatic increase in the level of ubiquitinated substrates in the ER membrane, and concomitantly, reduces extracted substrates in the cytoplasm. This work reveals a previously unrecognized regulatory mechanism in which ER membrane lipid remodeling controls the ERAD system.
