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Reference: Thakur JK, et al. (2009) Mediator Subunit Gal11p/MED15 Is Required for Fatty Acid-dependent Gene Activation by Yeast Transcription Factor Oaf1p. J Biol Chem 284(7):4422-8

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Abstract


The yeast zinc cluster transcription factor Oaf1p activates transcription of target genes in response to direct binding of fatty acids in a manner analogous to the vertebrate nuclear receptor peroxisome proliferator activated receptor alpha (PPARa). PPARs and other metazoan nuclear receptors productively engage several distinct LxxLL motif- containing co-activators, including p160 family members and the TRAP220/MED1 subunit of the Mediator, to promote ligand-dependent gene activation. Yeast, however, does not appear to harbor LxxLL-motif co-activators,and the mechanism of fatty acid-dependent gene activation by the yeast PPARa analog Oaf1p is unknown. Here we show that the yeast Mediator subunit Gal11p/MED15 and its activator-targeted KIX domain plays a critical role in fatty acid-dependent transcriptional regulation of fatty acid ss-oxidation and peroxisomal genes by Oaf1p, and for the ability of yeast to utilize fatty acids as a sole carbon source. Moreover, structural studies by NMR spectroscopy reveal that the Oaf1p activation domain interacts with the Gal11p/MED15 KIX domain in a manner similar to the yeast zinc cluster family member and xenobiotic receptor Pdr1p, revealing that the Gal11p/MED15 KIX domain is a key target of several ligand-dependent transcription factors in yeast. Together with previous work showing that the C. elegans Gal11p/MED15 homolog MDT-15 plays a critical role in regulation of fatty acid metabolism by the worm PPAR-like nuclear receptor NHR-49, the findings presented here provide evidence for an ancient and essential role of a Mediator co-activator subunit in regulation of fatty acid metabolism by nuclear receptor-like transcription factors in eukaryotes.

Reference Type
Journal Article
Authors
Thakur JK, Arthanari H, Yang F, Chau KH, Wagner G, Naar AM
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