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- Title
ATF6 modulates SREBP2-mediated lipogenesis.
- Authors
Lingfang Zeng; Min Lu; Kazutoshi Mori, Giacomo; Shengzhan Luo; Lee, Amy S.; Yi Zhu; Shyy, John Y-J.
- 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.
- Subjects
TRANSCRIPTION factors; STEROID-binding proteins; CARRIER proteins; PROTEIN synthesis; LIPID synthesis; CELL metabolism; MOLECULAR biology
- Publication
EMBO Journal, 2004, Vol 23, Issue 4, p950
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7600106