The stress-regulatory transcription factors Msn2 and Msn4 regulate fatty acid oxidation in budding yeast.

The transcription factors Msn2 and Msn4 (multicopy suppressor
of SNF1 mutation proteins 2 and 4) bind the stress-response
element in gene promoters in the yeast Saccharomyces
cerevisiae. However, the roles of Msn2/4 in primary metabolic
pathways such as fatty acid �-oxidation are unclear. Here,
in silico analysis revealed that the promoters of most genes
involved in the biogenesis, function, and regulation of the peroxisome
contain Msn2/4-binding sites.Wealso found that transcript
levels of MSN2/MSN4 are increased in glucose-depletion
conditions and that during growth in nonpreferred carbon
sources, Msn2 is constantly localized to the nucleus in wild-type
cells. Of note, the double mutant msn2�msn4� exhibited a
severe growth defect when grown with oleic acid as the sole carbon
source and had reduced transcript levels of major �-oxidation
genes. ChIP indicated that Msn2 has increased occupancy
on the promoters of�-oxidation genes in glucose-depleted conditions,
and in vivo reporter gene analysis indicated reduced
expression of these genes in msn2�msn4� cells. Moreover,
mobility shift assays revealed that Msn4 binds �-oxidation
gene promoters. Immunofluorescence microscopy with antiperoxisome
membrane protein antibodies disclosed that the
msn2�msn4� strain had fewer peroxisomes than the wild type,
and lipid analysis indicated that the msn2�msn4� strain had
increased triacylglycerol and steryl ester levels. Collectively, our
data suggest that Msn2/Msn4 transcription factors activate
expression of the genes involved in fatty acid oxidation. Because
glucose sensing, signaling, and fatty acid �-oxidation pathways
are evolutionarily conserved throughout eukaryotes, the msn2�
msn4�strain could therefore be a good model system for further
study of these critical processes.