1. Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA
2. Department of Cell Biology,
3. Department of Biological Chemistry and Molecular Pharmacology, and
4. Department of Pathology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
5. Institute of Biological Chemistry, Washington State University, Pullman, Washington 99164, USA
6. Bauer Center for Genomics Research, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA
7. Department of Molecular and Cell Biology, UC Berkeley, Berkeley, California 94720, USA
8. †Present addresses: Department of Genetics, Dartmouth Medical School, 7400 Remsen, Hanover, New Hampshire 03755, USA (R.M.S.); ERDC-CERL, PO Box 9005, Champaign, Illinois 61826-9005, USA (S.Y.); Prince George's Community College, 301 Largo Road, Largo, Maryland 20774, USA (C.M.); Utrecht University, Department of Developmental Biology, Kruytgebouw N305, Padualaan 8, 3584 CH, Utrecht, The Netherlands (S.v.d.H.)
9. *These authors contributed equally to this work

Correspondence to: Anders M. Näär^1,2 Correspondence and requests for materials should be addressed to A.M.N. (Email: naar@helix.mgh.harvard.edu). Atomic coordinates of the amino-terminal region of ARC105 containing the KIX domain has been deposited in the Protein Data Bank with the accession number 2GUT.

Abstract

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, 4, 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.

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