Nature 2006,
PMID: 16799563
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
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.
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Text Mining Data
Dashed line = No text mining data
Manually curated Databases
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IRef Biogrid Interaction:
CREBBP
—
KMT2A
(association, x-ray crystallography)
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IRef Biogrid Interaction:
CREBBP
—
MYB
(association, x-ray crystallography)
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IRef Biogrid Interaction:
SREBF1
—
CREBBP
(direct interaction, pull down)
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IRef Biogrid Interaction:
SREBF1
—
CREBBP
(colocalization, imaging technique)
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IRef Biogrid Interaction:
CREBBP
—
CREB1
(association, x-ray crystallography)
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IRef Biogrid Interaction:
SREBF1
—
MED15
(direct interaction, pull down)
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IRef Biogrid Interaction:
SREBF1
—
MED15
(association, x-ray crystallography)
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IRef Biogrid Interaction:
SREBF1
—
MED15
(colocalization, imaging technique)
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IRef Biogrid Interaction:
MED6
—
SREBF1
(direct interaction, pull down)
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IRef Biogrid Interaction:
MED26
—
SREBF1
(direct interaction, pull down)
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IRef Biogrid Interaction:
SREBF1
—
MED24
(direct interaction, pull down)
-
IRef Biogrid Interaction:
SREBF1
—
MED12
(direct interaction, pull down)
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IRef Biogrid Interaction:
MED13
—
SREBF1
(direct interaction, pull down)
-
IRef Biogrid Interaction:
SREBF1
—
MED23
(direct interaction, pull down)
-
IRef Biogrid Interaction:
MED14
—
SREBF1
(direct interaction, pull down)
-
IRef Biogrid Interaction:
MED1
—
SREBF1
(colocalization, imaging technique)
-
IRef Biogrid Interaction:
MED1
—
SREBF1
(direct interaction, pull down)
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IRef Biogrid Interaction:
SREBF1
—
MED25
(direct interaction, pull down)
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IRef Biogrid Interaction:
CDK8
—
SREBF1
(direct interaction, pull down)
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IRef Biogrid Interaction:
MED17
—
SREBF1
(direct interaction, pull down)
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IRef Biogrid Interaction:
MED1
—
THRA
(direct interaction, pull down)
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IRef Dip Interaction:
CREBBP
—
MYB
(physical association, pull down)
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IRef Intact Interaction:
MED15
—
SREBF1
(physical association, classical fluorescence spectroscopy)
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IRef Intact Interaction:
MED15
—
SREBF1
(physical association, pull down)
-
IRef Intact Interaction:
MED15
—
SREBF1
(physical association, anti tag coimmunoprecipitation)
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IRef Intact Interaction:
Complex of MED6-CREBBP-MED1-SREBF1-CDK8-MED15
(association, pull down)
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IRef Intact Interaction:
Complex of CREBBP-SREBF1-MED6-MED15-MED1-CDK8
(association, pull down)
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IRef Intact Interaction:
Complex of MED15-SREBF1
(association, pull down)
-
IRef Intact Interaction:
Complex of MED15-SREBF1
(association, pull down)
-
IRef Intact Interaction:
MED15
—
CREB1
(physical association, pull down)
-
IRef Intact Interaction:
MED1
—
THRA
(physical association, pull down)
-
IRef Intact Interaction:
MED15
—
MYB
(physical association, pull down)
-
IRef Intact Interaction:
Complex of MED1-CREBBP-SREBF2-MED6-CDK8-MED15
(association, pull down)
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IRef Intact Interaction:
Complex of MED15-SREBF2
(association, pull down)
In total, 34 gene pairs are associated to this article in curated databases