TY - JOUR
T1 - Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver
AU - Fusakio, Michael E.
AU - Willy, Jeffrey A.
AU - Wang, Yongping
AU - Mirek, Emily T.
AU - Baghdadi, Rana J.T.Al
AU - Adams, Christopher M.
AU - Anthony, Tracy G.
AU - Wek, Ronald C.
N1 - Funding Information:
This study was supported by National Institutes of Health Grants GM049164 (R.C.W.), HD070487 (T.G.A.), and AR059115 (C.M.A.), the Ralph W. and Grace M. Showalter Research Trust Fund (R.C.W.), Diabetes and Obesity Training Grant Diabetes Training Grant T32DK064466 (M.E.F.), and Veterans Affairs Grants BX00976 and RX001477 (C.M.A.).
Publisher Copyright:
© 2016 Zong et al.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
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U2 - 10.1091/mbc.E16-01-0039
DO - 10.1091/mbc.E16-01-0039
M3 - Article
C2 - 26960794
AN - SCOPUS:84964833362
SN - 1059-1524
VL - 27
SP - 1536
EP - 1551
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 9
ER -