Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

Michael E Fusakio; Jeffrey A Willy; Yongping Wang; Emily T Mirek; Rana J T Al Baghdadi; Christopher M Adams; Tracy G Anthony; Ronald C Wek

doi:10.1091/mbc.E16-01-0039

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Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

Journal article

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Peer reviewed

Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

Michael E Fusakio, Jeffrey A Willy, Yongping Wang, Emily T Mirek, Rana J T Al Baghdadi, Christopher M Adams, Tracy G Anthony and Ronald C Wek

Molecular biology of the cell, Vol.27(9), pp.1536-1551

05/01/2016

DOI: 10.1091/mbc.E16-01-0039

PMCID: PMC4850040

PMID: 26960794

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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.

Phosphorylation

Lipid Metabolism

Protein Folding

Cell Line

Transcription Factor CHOP - genetics

Protein Biosynthesis

Gene Expression - genetics

eIF-2 Kinase - metabolism

Liver - metabolism

Activating Transcription Factor 4 - genetics

Endoplasmic Reticulum - metabolism

Cholesterol - metabolism

Cholesterol - genetics

Mice, Knockout

Animals

Proteins - metabolism

Activating Transcription Factor 4 - metabolism

Endoplasmic Reticulum Stress

Transcription, Genetic

Mice

Transcription Factor CHOP - metabolism

Unfolded Protein Response - physiology

Details

Title: Subtitle: Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver
Creators: Michael E Fusakio - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
Jeffrey A Willy - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
Yongping Wang - Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901
Emily T Mirek - Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901
Rana J T Al Baghdadi - Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901
Christopher M Adams - Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa, and Iowa City Veterans Affairs Medical Center, Iowa City, IA 52246
Tracy G Anthony - Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901 rwek@iu.edu tracy.anthony@rutgers.edu
Ronald C Wek - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 rwek@iu.edu tracy.anthony@rutgers.edu
Resource Type: Journal article
Publication Details: Molecular biology of the cell, Vol.27(9), pp.1536-1551
DOI: 10.1091/mbc.E16-01-0039
PMID: 26960794
PMCID: PMC4850040
NLM abbreviation: Mol Biol Cell
ISSN: 1059-1524
eISSN: 1939-4586
Publisher: American Society for Cell Biology; United States
Grant note: I01 BX000976 / BLRD VA T32 DK064466 / NIDDK NIH HHS R01 GM049164 / NIGMS NIH HHS R01 HD070487 / NICHD NIH HHS R01 AR059115 / NIAMS NIH HHS I01 RX001477 / RRD VA
Language: English
Date published: 05/01/2016
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984025591402771

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