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An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis

Abstract

The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis1,2. We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes through unknown mechanisms3,4,5. Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by NMR revealed a three-helix bundle with marked similarity to the CBP/p300 KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The Caenorhabditis elegans SREBP homologue SBP-1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes6,7. We found that, like SBP-1, the C. elegans ARC105 homologue MDT-15 is required for fatty acid homeostasis, and show that both SBP-1 and MDT-15 control transcription of genes governing desaturation of stearic acid to oleic acid. Notably, dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against sbp-1 and mdt-15, including impaired intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of SBP-1 and MDT-15. Taken together, our findings demonstrate that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.

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Figure 1: The activation domains of SREBPs interact with the ARC105 subunit of the ARC/Mediator co-activator.
Figure 2: NMR solution structure of the ARC105 KIX domain.
Figure 3: ARC105 is required for SREBP-dependent transactivation and associates with SREBP target genes in human cells.
Figure 4: The C. elegans ARC105 homologue MDT-15 is a critical regulator of C. elegans SREBP (SBP-1) target genes and is required for normal lipid homeostasis.

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Acknowledgements

We were unable to cite many original papers owing to space constraints. We acknowledge G. Gill, N. Dyson and B. Spiegelman for comments on the manuscript. We thank B. Lüscher, R. Sordella and M. Classon for reagents, N. J. Moerke for his assistance with the fluorescence polarization experiments, and M. Dedmon for providing purified ARC105. A.M.N. is a Dammerman Scholar of the Damon Runyon Cancer Research Foundation. This work was supported by the NIH, the Damon Runyon Cancer Research Foundation, and the Milton Foundation of Harvard University.

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Correspondence to Anders M. Näär.

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Atomic coordinates of the amino-terminal region of ARC105 containing the KIX domain has been deposited in the Protein Data Bank with the accession number 2GUT. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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This file contains Supplementary Figures 1–9, Supplementary Tables 1 and 2, Supplementary Discussion, Supplementary Methods and additional references. (PDF 572 kb)

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Yang, F., Vought, B., Satterlee, J. et al. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 442, 700–704 (2006). https://doi.org/10.1038/nature04942

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