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

Abstract

The transcription factors Msn2 and Msn4 (multicopy suppressor of mutation proteins 2 and 4) bind the stress-response element in gene promoters in the yeast However, the roles of Msn2/4 in primary metabolic pathways such as fatty acid β-oxidation are unclear. Here, analysis revealed that the promoters of most genes involved in the biogenesis, function, and regulation of the peroxisome contain Msn2/4-binding sites. We also found that transcript levels of 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 ΔΔ exhibited a severe growth defect when grown with oleic acid as the sole carbon source and had reduced transcript levels of major β-oxidation genes. ChIP indicated that Msn2 has increased occupancy on the promoters of β-oxidation genes in glucose-depleted conditions, and reporter gene analysis indicated reduced expression of these genes inΔΔ cells. Moreover, mobility shift assays revealed that Msn4 binds β-oxidation gene promoters. Immunofluorescence microscopy with anti-peroxisome membrane protein antibodies disclosed that the ΔΔ strain had fewer peroxisomes than the wild type, and lipid analysis indicated that the ΔΔ 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 β-oxidation pathways are evolutionarily conserved throughout eukaryotes, the ΔΔ strain could therefore be a good model system for further study of these critical processes.

RTG Signaling Sustains Mitochondrial Respiratory Capacity in HOG1-Dependent Osmoadaptation

“…In this regard, considering the fact that Cit2 functions in the glyoxylate cycle, the relevance of peroxisomes in the adaptation of yeast cells to an osmotic environment is reinforced [ 18 ]. The low but significant increase in CIT2 expression under stress in RTG2 -lacking cells can be explained by additional regulatory mechanisms, including the up-regulation of this gene by Msn2/Msn4 under glucose-limiting conditions to support peroxisomal function [ 9 , 24 ] or through interaction with the carbon catabolite repression pathway [ 25 ].…”

Fermentation Efficiency of Genetically Modified Yeasts in Grapes Must

“…There is a concentration threshold for both of these, where the inactivation of Msn2/4 is reverted. It has been shown that yeast cells lacking Msn2 and Msn4 exhibit prevalent repression of glycolytic genes and a significant delay of acetyl-CoA accumulation and reentry into growth from quiescence as well as impaired expression of genes involved in the fatty acid oxidation and present an increment in triacylglycerol and steryl ester levels [8,9]. As the depletion of these transcription factors seems to affect the metabolic function of the cell, a more targeted intervention to PKA/Msn2/4 system may contribute to the improvement of alcoholic fermentation.…”

Phenomic screen identifies a role for the yeast lysine acetyltransferase NuA4 in the control of Bcy1 subcellular localization, glycogen biosynthesis, and mitochondrial morphology

“…One key downstream effect of Tpk activity is the regulation of the localization of the functionally redundant Msn2 and Msn4 (Msn2/4) stress response transcription factors which are phosphorylated and sequestered in the cytoplasm [43,44]. Upon stress or inhibition of PKA activity, Msn2/Msn4 phosphorylation decreases allowing for translocation into the nucleus where they bind to stress response elements (STREs) and activate transcription of genes related to β oxidation of fatty acids, glycolysis, and stress response [45][46][47]. Interestingly, Msn2/4-dependent transcription is de-repressed in NuA4 mutants [20].…”