Yang Fajun, Vought Bryan W, Satterlee John S, Walker Amy K, Jim Sun Z-Y, Watts Jennifer L, DeBeaumont Rosalie, Saito R Mako, Hyberts Sven G, Yang Shaosong, Macol Christine, Iyer Lakshmanan, Tjian Robert, van den Heuvel Sander, Hart Anne C, Wagner Gerhard, Näär Anders M
Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA.
Nature. 2006 Aug 10;442(7103):700-4. doi: 10.1038/nature04942. Epub 2006 Jun 21.
The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis. 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. 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. 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.
转录激活因子固醇调节元件结合蛋白（SREBP）家族是胆固醇和脂肪酸稳态的关键调节因子。我们先前证明，人类SREBP与CREB结合蛋白（CBP）/p300乙酰转移酶KIX结构域结合，并通过未知机制募集激活因子募集辅因子（ARC）/中介体共激活复合物。在此我们表明，SREBP利用进化上保守的ARC105（也称为MED15）亚基来激活靶基因。通过核磁共振对ARC105中SREBP结合结构域进行的结构分析揭示了一个三螺旋束，与CBP/p300 KIX结构域具有显著相似性。与SREBP不同，CREB和c-Myb激活因子不与ARC105 KIX结构域结合，尽管它们与CBP KIX结构域相互作用，这揭示了在结构相关的激活因子结合结构域之间存在惊人的特异性。秀丽隐杆线虫SREBP同源物SBP-1通过调节生脂酶的表达来促进脂肪酸稳态。我们发现，与SBP-1一样，秀丽隐杆线虫ARC105同源物MDT-15是脂肪酸稳态所必需的，并表明SBP-1和MDT-15都控制着将硬脂酸去饱和为油酸的基因的转录。值得注意的是，饮食中添加油酸显著挽救了用RNA干扰靶向sbp-1和mdt-15的线虫的各种缺陷，包括肠道脂肪储存受损、不育、体型减小和运动缓慢，这表明调节油酸水平代表了SBP-1和MDT-15的一项生理关键功能。综上所述，我们的研究结果表明，ARC105是后生动物中SREBP依赖性基因调控和脂质稳态控制的关键效应因子。
