CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4.
3T3 Cells
Acyltransferases
/ genetics
Animals
Caenorhabditis elegans
/ genetics
Caenorhabditis elegans Proteins
/ genetics
Calcium-Binding Proteins
/ genetics
Cell Proliferation
Drosophila Proteins
/ genetics
Drosophila melanogaster
Endoplasmic Reticulum
/ drug effects
Enzyme Activation
Gene Expression Regulation, Enzymologic
Glycerides
/ biosynthesis
Glycerol-3-Phosphate O-Acyltransferase
/ genetics
HEK293 Cells
HeLa Cells
Hep G2 Cells
Humans
Jurkat Cells
Lipogenesis
/ drug effects
Mice
Palmitic Acid
/ toxicity
Protein Binding
CHP1
CRISPR
GPAT4
cellular metabolism
fatty acids
genetic screens
glycerolipid synthesis
lipid metabolism
lipidomics
triacylglycerol accumulation
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
04 04 2019
04 04 2019
Historique:
received:
28
06
2018
revised:
26
11
2018
accepted:
25
01
2019
pubmed:
9
3
2019
medline:
16
7
2019
entrez:
9
3
2019
Statut:
ppublish
Résumé
Cells require a constant supply of fatty acids to survive and proliferate. Fatty acids incorporate into membrane and storage glycerolipids through a series of endoplasmic reticulum (ER) enzymes, but how these enzymes are regulated is not well understood. Here, using a combination of CRISPR-based genetic screens and unbiased lipidomics, we identified calcineurin B homologous protein 1 (CHP1) as a major regulator of ER glycerolipid synthesis. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. Mechanistically, CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis. GPAT4 activity requires CHP1 to be N-myristoylated, forming a key molecular interface between the two proteins. Interestingly, upon CHP1 loss, the peroxisomal enzyme, GNPAT, partially compensates for the loss of ER lipid synthesis, enabling cell proliferation. Thus, our work identifies a conserved regulator of glycerolipid metabolism and reveals plasticity in lipid synthesis of proliferating cells.
Identifiants
pubmed: 30846317
pii: S1097-2765(19)30057-7
doi: 10.1016/j.molcel.2019.01.037
pmc: PMC6450717
mid: NIHMS1520445
pii:
doi:
Substances chimiques
CHP1 protein, human
0
Caenorhabditis elegans Proteins
0
Calcium-Binding Proteins
0
Drosophila Proteins
0
Glycerides
0
Palmitic Acid
2V16EO95H1
Acyltransferases
EC 2.3.-
GPAT4 protein, human
EC 2.3.1.15
Glycerol-3-Phosphate O-Acyltransferase
EC 2.3.1.15
glycerone-phosphate O-acyltransferase
EC 2.3.1.42
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
45-58.e7Subventions
Organisme : NCI NIH HHS
ID : K22 CA193660
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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