title: 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 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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA.
authors.forename: Fajun
authors.initials: F
authors.lastname: Yang
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Vought
authors.forename: John S
authors.initials: JS
authors.lastname: Satterlee
authors.forename: Amy K
authors.initials: AK
authors.lastname: Walker
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Jim Sun
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Watts
authors.forename: Rosalie
authors.initials: R
authors.lastname: DeBeaumont
authors.forename: R Mako
authors.initials: RM
authors.lastname: Saito
authors.forename: Sven G
authors.initials: SG
authors.lastname: Hyberts
authors.forename: Shaosong
authors.initials: S
authors.lastname: Yang
authors.forename: Christine
authors.initials: C
authors.lastname: Macol
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Iyer
authors.forename: Robert
authors.initials: R
authors.lastname: Tjian
authors.forename: Sander
authors.initials: S
authors.lastname: van den Heuvel
authors.forename: Anne C
authors.initials: AC
authors.lastname: Hart
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Anders M
authors.initials: AM
authors.lastname: Näär
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D056892:Mediator Complex; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051779:Sterol Regulatory Element Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C513281:ARC105 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C416944:MED15 protein, human; D056892:Mediator Complex; C513283:SBP-1 protein, C elegans; D051779:Sterol Regulatory Element Binding Proteins; D014157:Transcription Factors; D002784:Cholesterol