ATF6 modulates SREBP2-mediated lipogenesis.
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.
Zeng
Lingfang
L
Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121, USA.
Lu
Min
M
Mori
Kazutoshi
K
Luo
Shengzhan
S
Lee
Amy S
AS
Zhu
Yi
Y
Shyy
John Y-J
JY
D051702:Activating Transcription Factor 6; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose / Q000172:deficiency; D006360:Heat-Shock Proteins / Q000378:metabolism; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D016350:Leucine Zippers; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008055:Lipids; D018832:Molecular Chaperones; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D005947:Glucose