Article
- The EMBO Journal (2004) 23, 950 - 958
- doi:10.1038/sj.emboj.7600106
Published online: 5 February 2004
Subject Categories:
ATF6 modulates SREBP2-mediated lipogenesis
Lingfang Zeng1, Min Lu1, Kazutoshi Mori2, Shengzhan Luo3, Amy S Lee3, Yi Zhu1 and John Y-J Shyy1
- Division of Biomedical Sciences, University of California, Riverside, Riverside, CA, USA
- Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Department of Biochemistry and Molecular Biology and the USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Correspondence to:
John Y-J Shyy, Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA. Tel.: +1 909 787 3863; Fax: +1 909 787 5504; E-mail: john.shyy@ucr.edu
Received 1 September 2003; Accepted 8 January 2004
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.
Keywords:
- ATF6,
- ER stress,
- glucose starvation,
- lipogenesis,
- SREBP2
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