An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.
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.
Yang
Fajun
F
Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA.
Vought
Bryan W
BW
Satterlee
John S
JS
Walker
Amy K
AK
Jim Sun
Z-Y
ZY
Watts
Jennifer L
JL
DeBeaumont
Rosalie
R
Saito
R Mako
RM
Hyberts
Sven G
SG
Yang
Shaosong
S
Macol
Christine
C
Iyer
Lakshmanan
L
Tjian
Robert
R
van den Heuvel
Sander
S
Hart
Anne C
AC
Wagner
Gerhard
G
Näär
Anders M
AM
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
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