Drosophila melanogasterActivating Transcription Factor 4 Regulates Glycolysis During Endoplasmic Reticulum Stress
Authors:
Open Access
- 1 April 2015
- journal article
- Published by Oxford University Press (OUP) in G3: Genes, Genomes, Genetics
- Vol. 5 (4) , 667-675
Abstract
Endoplasmic reticulum (ER) stress results from an imbalance between the load of proteins entering the secretory pathway and the ability of the ER to fold and process them. The response to ER stress is mediated by a collection of signaling pathways termed the unfolded protein response (UPR), which plays important roles in development and disease. Here we show that in Drosophila melanogaster S2 cells, ER stress induces a coordinated change in the expression of genes involved in carbon metabolism. Genes encoding enzymes that carry out glycolysis were up-regulated, whereas genes encoding proteins in the TCA cycle and respiratory chain complexes were down-regulated. The UPR transcription factor Atf4 was necessary for the up-regulation of glycolytic enzymes and Lactate dehydrogenase (Ldh). Furthermore, Atf4 binding motifs in promoters for these genes could partially account for their regulation during ER stress. Finally, flies up-regulated Ldh and produced more lactate when subjected to ER stress. Together these results suggest that Atf4 mediates a shift from a metabolism based on oxidative phosphorylation to one more heavily reliant on glycolysis, reminiscent of aerobic glycolysis or the Warburg effect observed in cancer and other proliferative cells.Keywords
This publication has 65 references indexed in Scilit:
- Glucose starvation induces cell death in K-ras-transformed cells by interfering with the hexosamine biosynthesis pathway and activating the unfolded protein responseCell Death & Disease, 2013
- ER-stress-induced transcriptional regulation increases protein synthesis leading to cell deathNature Cell Biology, 2013
- The Drosophila Estrogen-Related Receptor Directs a Metabolic Switch that Supports Developmental GrowthCell Metabolism, 2011
- Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stressCell Death & Differentiation, 2010
- 2-Deoxy-d-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletionCancer Chemotherapy and Pharmacology, 2010
- An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative StressMolecular Cell, 2003
- IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNANature, 2002
- XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription FactorCell, 2001
- A transmembrane protein with a cdc2+CDC28-related kinase activity is required for signaling from the ER to the nucleusCell, 1993
- Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinaseCell, 1993