Lipid Homeostasis Is Essential for Endoplasmic Reticulum Protein Quality Control

The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, protein trafficking, and lipid synthesis. As such, cells have evolved a quality control system known as the ER Unfolded Protein Response (UPRER). Capable of monitoring protein folding and membrane lipid composition to preserve ER homeostasis, the UPRER is crucial for responding to cellular stress brought on by increased metabolic demand, environmental factors, and aging. In this study, we have identified let-767 as an essential gene for ER homeostasis. Through an RNAi screen of lipid droplet associated genes, we found that knockdown of let-767 resulted in reduced lipid droplets, aberrant ER morphology, and compromised UPRER induction, which impacted growth and lifespan. We found that these deficiencies in ER quality were independent of let-767’s previously characterized function in mono-methyl branched chain fatty acid synthesis (mmBCFAs), as supplementation of mmBCFAs did not ameliorate the detrimental phenotypes. However, supplementation of whole animal lysate was able to rescue the lipid droplet depletion, ER morphology, and animal growth, but not the UPRER function. The UPRER induction was instead rescued by reducing the let-767 pathway through knockdown of the upstream transcription factor sbp-1, suggesting accumulation of a potential toxic metabolite within the let-767 pathway. Our results indicate that let-767 may play a more significant role in lipid metabolism than has been previously described and highlight the importance of lipid homeostasis to protein quality control