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

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

doi:10.1091/mbc.e16-01-0039

Cited by 180 publications

(154 citation statements)

References 80 publications

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“…7). Our data agree with the observations from global transcriptional profiling, which showed significantly reduced Zip14 mRNA levels after TM treatment in liver-specific Atf4 −/− mice (35) and in Atf6α −/− fibroblasts (34). ATF4 and ATF6α regulation of Zip14 suggests that these events lead to increased cellular zinc availability through ZIP14-mediated zinc transport.…”

Section: Discussionsupporting

confidence: 92%

“…Genetic ablations of UPR components, including ATF6α, IRE1α, and eIF2α, result in the development of hepatic steatosis (14,54,55). Loss of ATF4 increased free cholesterol in rodent liver (35), and liver-specific deletion of XBP1 produced hypocholesterolemia and hypotriglyceridemia (56). Similar to these observations, the liver of Zip14 KO mice showed potentiated TG accumulation after TM administration due to enhanced FA synthesis (Fig.…”

Section: Discussionsupporting

confidence: 63%

“…7B). Global gene expression screening data provided clues regarding the potential Zip14-regulating transcription factors ATF4 and ATF6α (34,35). ATF4 and ATF6α have been shown to have a strong binding affinity to the Immunoblot analysis of ER stress markers from liver lysates of WT and KO mice (n = 4, pooled samples used).…”

Section: Tm Administration Alters Hepatic Zinc Homeostasis and Zinc Tmentioning

confidence: 99%

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Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

Kim

Aydemir

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14 −/− (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.unfolded protein response | p-eIF2α/ATF4/CHOP pathway | apoptosis | steatosis | zinc metabolism

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 63%

Section: Tm Administration Alters Hepatic Zinc Homeostasis and Zinc Tmentioning

confidence: 99%

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Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

Kim

Aydemir

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In all the cases, these increases in mRNA levels were observed no earlier than 3 h following the injection of asparaginase, again confirming that acute inhibition of mTORC1 does not involve an ATF4-driven transcriptional program. Interestingly, our previous studies show that induction of Trib3 mRNA by asparaginase requires GCN2, but not ATF4, as Atf4 -/-animals treated with asparaginase demonstrate 10-fold greater increases in Trib3 mRNA levels to asparaginase than wild type animals, whereas no induction whatsoever is observed in Gcn2 -/-animals (8,32). This confirms that Trib3 gene is controlled by other transcriptional factors in addition to ATF4 (18), but whether TRIB3 represents the major effector of GCN2 pathway that contributes to sustained inhibition of hepatic mTORC1 in WT, as well as in Atf4 -/-animals requires further investigation.…”

Section: Discussionmentioning

confidence: 92%

Time-resolved analysis of amino acid stress identifies eIF2 phosphorylation as necessary to inhibit mTORC1 activity in liver

Nikonorova

Mirek

Signore

et al. 2018

Journal of Biological Chemistry

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“…3A). Lack of appropriate GCN4 and ATF4 expression renders cells susceptible to nutrient deficiencies and oxidative damage (32,46,50).…”

Section: Delayed Translation Reinitiationmentioning

confidence: 99%

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

Young

Wek

2016

Journal of Biological Chemistry

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332

313

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Translation regulation largely occurs during initiation, which features ribosome assembly onto mRNAs and selection of the translation start site. Short, upstream ORFs (uORFs) located in the 5-leader of the mRNA can be selected for translation. Multiple transcripts associated with stress amelioration are preferentially translated through uORF-mediated mechanisms during activation of the integrated stress response (ISR) in which phosphorylation of the ␣ subunit of eIF2 results in a coincident global reduction in translation initiation. This review presents key features of uORFs that serve to optimize translational control that is essential for regulation of cell fate in response to environmental stresses.Multiple genome-wide analyses, including those utilizing ribosome and polysome profiling and mass spectrometry approaches, have provided evidence demonstrating that translation is a major regulator of gene expression (1-5). In addition to protein coding sequences (CDSs), 2 another class of ORFs suggested to be translated at high frequency consists of short, upstream ORFs (uORFs) that are located within the 5Ј-leader of mRNAs (3-6). Over 40% of mammalian mRNAs contain uORFs, illustrating that uORFs are prevalent genome-wide and can serve as major regulators of translation (5,7,8). Approximation of uORF prevalence has relied upon the use of an AUG to denote the uORF start codon; however, recent ribosome profiling studies indicate that non-canonical initiation codons (e.g. CUG, UUG, and GUG) can also serve as competent sites of translation initiation (3, 4, 6). These findings suggest that the magnitude of uORF prevalence and the contribution of uORF translation in the regulation of gene expression have likely been underestimated.Typically, uORFs are considered to be inhibitors of downstream translation initiation at CDSs. The inhibitory effect of uORFs is attributed to the fact that in eukaryotes the 43S preinitiation complex binds to the 5Ј-cap structure of the mRNA, then scans processively 5Ј to 3Ј and initiates translation at the first encountered initiation codon that is in an optimal context (9). The 43S preinitiation complex is composed of multiple factors including eIF3, eIF1, eIF1A, the eIF2⅐GTP⅐Met-tRNA i Met ternary complex, and the small 40S ribosomal subunit (10). Disassociation of the eIF2 ternary complex and other critical initiation factors during translation of constitutively repressing uORFs is suggested to be the cause of the low levels of subsequent translation reinitiation at downstream coding sequences.Although uORFs can serve as repressors of CDS translation in a constitutive manner, there are also examples of uORFs that serve as dampeners in a controlled fashion or even promote translation initiation at the CDS in response to environmental stresses (4, 5, 11). Based on these studies, uORFs can have the following core properties that are critical for translational control (Fig. 1). 1) They enhance reinitiation after uORF translation, allowing for degrees of translation initiation at the downstre...

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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

Cited by 180 publications

References 80 publications

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

Time-resolved analysis of amino acid stress identifies eIF2 phosphorylation as necessary to inhibit mTORC1 activity in liver

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

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