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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ATF6 modulates SREBP2-mediated lipogenesis

^{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}

^{Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA. Tel.: +1 909 787 3863; Fax: +1 909 787 5504; E-mail:}ude.rcu@yyhs.nhoj

Received 2003 Sep 1; Accepted 2004 Jan 8.

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

Abstract

Acknowledgments

This study was supported in part by NIH grants HL56707, HL60789 (JS) from the National Heart, Lung, and Blood Institute, grant CA27607 (ASL) from the National Cancer Institute, and grant 15GS0310 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KM). We thank Jianze Li for plasmid construction. JY-JS is an established investigator of the American Heart Association.

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