ATF4 Responds to Metabolic Stress in Drosophila

Abstract

Background: Activating transcription factor 4 (ATF4) is a fundamental basic-leucine zipper transcription factor that plays a pivotal role in numerous stress responses, including endoplasmic reticulum (ER) stress and the integrated stress response. ATF4 regulates adaptive gene expression, thereby triggering stress resistance in cells. Methods: To characterize the metabolic status of atf4-⁣/- Drosophila larvae, we conducted both metabolomic and microarray analyses. Results: Metabolomic analysis demonstrated an increase in lactate levels in atf4-⁣/- mutants when compared to wild-type flies. However, there was a significant reduction in adenosine triphosphate (ATP) synthesis in the atf4-⁣/- flies, suggesting an abnormal energy metabolism in the mutant larvae. Microarray analysis unveiled that Drosophila ATF4 controls gene expression related to diverse biological processes, including lipase activity, oxidoreductase activity, acyltransferase, immune response, cell death, and transcription factor, particularly under nutrient-restricted conditions. In situ hybridization analysis further demonstrated specific augmentation of CG6283, classified as a gastric lipase, within the gastric caeca of nutrient-restricted flies. Moreover, overexpression of lipases, CG6283 and CG6295, made the flies resistant to starvation. Conclusions: These findings underscore the role of Drosophila ATF4 in responding to metabolic fluctuations and modulating gene expression associated with metabolism and stress adaptation. Dysregulation of ATF4 may detrimentally impact the development and physiology of Drosophila.

Keywords

• atf4
• integrated stress response
• nutrient restriction
• lipase
• microarray
• drosophila