Dataset Information

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 identified let-767, a putative hydroxysteroid dehydrogenase in Caenorhabditis elegans, 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 blocks induction of the Unfolded Protein Response of the ER (UPR^ER). Interestingly, a global reduction in lipogenic pathways restores UPR^ER 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 UPR^ER. This study highlights a novel interaction through which changes in lipid metabolism can alter a cell's response to protein-induced stress.

SUBMITTER: Garcia G

PROVIDER: S-EPMC10368420 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lipid homeostasis is essential for a maximal ER stress response.

Garcia Gilberto G Zhang Hanlin H Moreno Sophia S Tsui C Kimberly CK Webster Brant Michael BM Higuchi-Sanabria Ryo R Dillin Andrew A

eLife 20230725

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 identified <i>let-767</i>, a putative hydroxysteroid dehydrogenase in <i>Caenorhabditis elegans</i>, as an essential gene for both lipid a ...[more]

PMID: 37489956

Similar Datasets

Project description:Glycerophospholipids including phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are vital components of biological membranes. Trypanosomatid parasites of the genus Leishmania can acquire PE and PC via de novo synthesis and the uptake/remodeling of host lipids. In this study, we investigated the ethanolaminephosphate cytidyltransferase (EPCT) in Leishmania major , which is the causative agent for cutaneous leishmaniasis. EPCT is a key enzyme in the ethanolamine branch of the Kennedy pathway which is responsible for the de novo synthesis of PE. Our results demonstrate that L. major EPCT is a cytosolic protein capable of catalyzing the formation of CDP-ethanolamine from ethanolamine-phosphate and cytidine triphosphate. Genetic manipulation experiments indicate that EPCT is essential in both the promastigote and amastigote stages of L. major as the chromosomal null mutants cannot survive without the episomal expression of EPCT. This differs from our previous findings on the choline branch of the Kennedy pathway (responsible for PC synthesis) which is required only in promastigotes but not amastigotes. While episomal EPCT expression does not affect promastigote proliferation under normal conditions, it leads to reduced production of ethanolamine plasmalogen or plasmenylethanolamine, the dominant PE subtype in Leishmania . In addition, parasites with epsiomal EPCT exhibit heightened sensitivity to acidic pH and starvation stress, and significant reduction in virulence. In summary, our investigation demonstrates that proper regulation of EPCT expression is crucial for PE synthesis, stress response, and survival of Leishmania parasites throughout their life cycle.Author summaryIn nature, Leishmania parasites alternate between fast replicating, extracellular promastigotes in sand fly gut and slow growing, intracellular amastigotes in macrophages. Previous studies suggest that promastigotes acquire most of their lipids via de novo synthesis whereas amastigotes rely on the uptake and remodeling of host lipids. Here we investigated the function of ethanolaminephosphate cytidyltransferase (EPCT) which catalyzes a key step in the de novo synthesis of phosphatidylethanolamine (PE) in Leishmania major . Results showed that EPCT is indispensable for both promastigotes and amastigotes, indicating that de novo PE synthesis is still needed at certain capacity for the intracellular form of Leishmania parasites. In addition, elevated EPCT expression alters overall PE synthesis and compromises parasiteâ€™s tolerance to adverse conditions and is deleterious to the growth of intracellular amastigotes. These findings provide new insight into how Leishmania acquire essential phospholipids and how disturbance of lipid metabolism can impact parasite fitness.

Dataset Information

Lipid homeostasis is essential for a maximal ER stress response.

Publications

Lipid homeostasis is essential for a maximal ER stress response.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets