Lipid homeostasis is essential for a maximal ER stress response

Abstract

Changes in lipid metabolism are associated with aging and age-related diseases, including proteopathies. The endoplasmic reticulum (ER) is uniquely a major hub for protein and lipid synthesis, making its function essential for both protein and lipid homeostasis. However, it is less clear how lipid metabolism and protein quality may impact each other. Here, we identity let-767, a putative hydroxysteroid dehydrogenase, as an essential gene for both lipid and ER protein homeostasis. Knockdown of let-767 reduces lipid stores, alters ER morphology in a lipid-dependent manner, and also blocks induction of the Unfolded Protein Response of the ER (UPRER). Interestingly, a global reduction in lipogenic pathways restores UPRER induction in animals with reduced let-767. Specifically, we find that supplementation of 3-oxoacyl, the predicted metabolite directly upstream of let-767, is sufficient to block induction of the UPRER. This study highlights a novel interaction through which changes in lipid metabolism can alter a cell's response to protein-induced stress.

Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis

“…Proper UPR ER signaling is reliant on the dimer/oligomerization of IRE1, which differentially splices xbp-1 mRNA to its active form xbp-1 s. To investigate the impact of hsp-6 knockdown on ectopic UPR ER activation at two different points within the same pathway, we used 1) overexpression of IRE1, which would require proper IRE1 dimer/oligomerization, and 2) overexpression of xbp-1 s (active form of xbp-1 ), allowing for the bypass of IRE1 dimer/oligomerization. Overexpression of IRE1 lacking the luminal domain ( ire-1 (344-967aa)) in the intestine induced UPR ER signaling 24 . This induction was moderately reduced upon hsp-6 knockdown.…”

“…To investigate the impact of mtHSP70 knockdown on ectopic UPR ER activation at two different points within the same pathway, we used 1) overexpression of IRE1 lacking the luminal domain, which activates UPR ER in the absence of proteotoxic stress but still requires proper dimer/oligomerization and 2) overexpression of xbp-1s (active form of xbp-1), allowing for the bypass of IRE1 dimer/oligomerization. Overexpression of IRE1 lacking the luminal domain (ire-1 (344-967aa)) in the intestine induced UPR ER signaling 25 . This induction was moderately reduced upon mtHSP70 knockdown while mtHSP70 knockdown had no impact on xbp-1s overexpression-induced UPR ER (Figure 3b).…”

An eQTL-based Approach Reveals Candidate Regulators of LINE-1 RNA Levels in Lymphoblastoid Cells

“…For these two candidates, cells may be more sensitive to knockdown-or knockout-based approaches. Indeed, HSD17B12 is essential for mouse development, HSD17B12 knockout in adult mice results in reduced body weight and liver toxicity, and knockdown of the Caenorhabditis elegans ortholog for HSD17B12 reduces lipid stores and blocks induction of the unfolded protein response of the endoplasmic reticulum [52,74,75]. Given that TEs are often derepressed when homeostasis is challenged [61], such as following HSD17B12 knockout/knockdown, it remains possible that HSD17B12 possesses L1 regulatory properties that were not detectable by our approach.…”