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ATF6 modulates SREBP2-mediated lipogenesis.

Lingfang Zeng·Min Lu·Kazutoshi Mori·Shengzhan Luo·Amy S Lee·Yi Zhu·John Y-J Shyy
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Abstract

Activating transcription factor 6 (ATF6) and sterol regulatory element-binding proteins (SREBPs) are activated by proteolytic cleavage. The ensuing nuclear translocation of their N-termini (i.e., ATF6(N) and SREBP(N)) activates the respective target genes involved in unfolded protein response and lipogenesis. Here, we report that glucose deprivation activated ATF6 but suppressed the SREBP2-regulated transcription. Overexpression of ATF6(N) had similar inhibitory effects on SREBP2-targeted genes. The blockade of ATF6 cleavage by BiP/grp78 reversed this inhibitory effect. GST pull-down and immunoprecipitation assays revealed that ATF6(N) bound to SREBP2(N). Deletion analysis of the various functional domains of ATF6 indicated that the interaction was through its leucine-zipper domain. Chromatin immunoprecipitation assays revealed that ATF6(N) formed a complex with the SRE-bound SREBP2(N). The attenuated transcriptional activity of SREBP2 was due, in part, to the recruitment of HDAC1 to the ATF6-SREBP2 complex. As a functional consequence, the lipogenic effect of SREBP2(N) in liver cells was suppressed by ATF6(N). Our results provide a novel mechanism by which ATF6 antagonizes SREBP2 to regulate the homeostasis of lipid and glucose.

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Activating Transcription Factor 6Cell DifferentiationCells, CulturedChromatin ImmunoprecipitationDNA-Binding ProteinsEndoplasmic Reticulum Chaperone BiPGlucoseHeat-Shock ProteinsHistone Deacetylase 1Histone DeacetylasesHumansLeucine ZippersLipidsLiverMolecular ChaperonesMutationProtein BindingProtein TransportSterol Regulatory Element Binding Protein 2Transcription FactorsTranscription, GeneticTranscriptional ActivationJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

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Lingfang Zeng, Min Lu, Kazutoshi Mori, Shengzhan Luo, Amy S Lee, Yi Zhu, John Y-J Shyy. 2004-02-05. ATF6 modulates SREBP2-mediated lipogenesis.. https://doi.org/10.1038/sj.emboj.7600106

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