title: Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver.
abstract: Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins-PERK (PEK/EIF2AK3), IRE1, and ATF6-is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Fusakio
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Willy
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901.
authors.forename: Emily T
authors.initials: ET
authors.lastname: Mirek
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901.
authors.forename: Rana J T
authors.initials: RJ
authors.lastname: Al Baghdadi
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa, and Iowa City Veterans Affairs Medical Center, Iowa City, IA 52246.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901 rwek@iu.edu tracy.anthony@rutgers.edu.
authors.forename: Tracy G
authors.initials: TG
authors.lastname: Anthony
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 rwek@iu.edu tracy.anthony@rutgers.edu.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression / Q000235:genetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D056811:Unfolded Protein Response / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C081452:Atf4 protein, mouse; D011506:Proteins; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D002784:Cholesterol; D019892:eIF-2 Kinase