CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis

• Published in: Molecular biology of the cell Vol. 24; no. 15; pp. 2477 - 2490
• Main Authors: Teske, Brian F., Fusakio, Michael E., Zhou, Donghui, Shan, Jixiu, McClintick, Jeanette N., Kilberg, Michael S., Wek, Ronald C.
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 01.08.2013
• Subjects: Activating Transcription Factors - genetics; Activating Transcription Factors - metabolism; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cell Survival; Cells, Cultured; Eukaryotic Initiation Factor-2 - metabolism; Feedback, Physiological; Gene Expression Regulation; Gene Knockout Techniques; Gene Regulatory Networks; Homeostasis; Leupeptins - pharmacology; Mice; Phosphorylation; Promoter Regions, Genetic; Proteasome Inhibitors - pharmacology; Protein Biosynthesis; Protein Processing, Post-Translational; Proteolysis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Response Elements; Stress, Physiological; Thapsigargin - pharmacology; Transcription Factor CHOP - physiology; Transcriptional Activation; Transcriptome
• DOI: 10.1091/mbc.e13-01-0067
• ISSN: 1059-1524; 1939-4586

Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switches to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study is to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP enhances the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly induced by both CHOP and ATF4. Knockdown of ATF5 increases cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have proapoptotic functions. Transcriptome analysis of ATF5-dependent genes reveals targets involved in apoptosis, including NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feedforward loop of stress-induced transcriptional regulators, each subject to transcriptional and translational control, which can switch cell fate toward apoptosis.