An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.
Yang, Fajun 1,2*; Vought, Bryan W. 3*; Satterlee, John S. 1; Walker, Amy K. 1,4; Sun, Z.-Y. Jim 3; Watts, Jennifer L. 5; DeBeaumont, Rosalie 1,2; Saito, R. Mako 1,4+; Hyberts, Sven G. 3; Yang, Shaosong 1,2+; Macol, Christine 1,2+; Iyer, Lakshmanan 6; Tjian, Robert 7; van den Heuvel, Sander 1,4+; Hart, Anne C. 1,4; Wagner, Gerhard 3; Naar, Anders M. 1,2
[Letter]
Nature.
442(7103):700-704, August 10, 2006.
(Format: HTML, PDF)
The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis 1,2. 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 mechanisms 3-5. 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 enzymes 6,7. 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.
(C) 2006 Nature Publishing Group