title: Drosophila melanogaster activating transcription factor 4 regulates glycolysis during endoplasmic reticulum stress.
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, 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 tricarboxylic acid cycle and respiratory chain complexes were down-regulated. The unfolded protein response 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.
authors: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors: Ji Eun
authors: JE
authors: Lee
authors: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors: McKenna
authors: M
authors: Oney
authors: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors: Kimberly
authors: K
authors: Frizzell
authors: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors: Nitin
authors: N
authors: Phadnis
authors: Department of Biology, University of Utah, Salt Lake City, Utah 84112 hollien@biology.utah.edu.
authors: Julie
authors: J
authors: Hollien
mesh_terms: D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002952:Citric Acid Cycle / Q000235:genetics; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D025221:Phosphofructokinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; D009097:Multienzyme Complexes; D012330:RNA, Double-Stranded; D051701:Activating Transcription Factor 4; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D025221:Phosphofructokinases; D010100:Oxygen
keywords: Atf4; endoplasmic reticulum stress; glycolysis; metabolism; unfolded protein response