Mga2 Transcription Factor Regulates an Oxygen-responsive Lipid Homeostasis Pathway in Fission Yeast

Abstract

Eukaryotic lipid synthesis is oxygen-dependent with cholesterol synthesis requiring 11 oxygen molecules and fatty acid desaturation requiring 1 oxygen molecule per double bond. Accordingly, organisms evaluate oxygen availability to control lipid homeostasis. The sterol regulatory element-binding protein (SREBP) transcription factors regulate lipid homeostasis. In mammals, SREBP-2 controls cholesterol biosynthesis, whereas SREBP-1 controls triacylglycerol and glycerophospholipid biosynthesis. In the fission yeast Schizosaccharomyces pombe, the SREBP-2 homolog Sre1 regulates sterol homeostasis in response to changing sterol and oxygen levels. However, notably missing is an SREBP-1 analog that regulates triacylglycerol and glycerophospholipid homeostasis in response to low oxygen. Consistent with this, studies have shown that the Sre1 transcription factor regulates only a fraction of all genes up-regulated under low oxygen. To identify new regulators of low oxygen adaptation, we screened the S. pombe nonessential haploid deletion collection and identified 27 gene deletions sensitive to both low oxygen and cobalt chloride, a hypoxia mimetic. One of these genes, mga2, is a putative transcriptional activator. In the absence of mga2, fission yeast exhibited growth defects under both normoxia and low oxygen conditions. Mga2 transcriptional targets were enriched for lipid metabolism genes, and mga2⌬ cells showed disrupted triacylglycerol and glycerophospholipid homeostasis, most notably with an increase in fatty acid saturation. Indeed, addition of exogenous oleic acid to mga2⌬ cells rescued the observed growth defects. Together, these results establish Mga2 as a transcriptional regulator of triacylglycerol and glycerophospholipid homeostasis in S. pombe, analogous to mammalian SREBP-1.

Control of membrane fluidity: the OLE pathway in focus

“…In this light, the ER-membrane serves as 'memory device' to integrate a long-term signal for oxygen availability, which is encoded by the lipid composition (Covino et al, 2016;Ernst et al, 2016). This elegant mechanism of signal integration is apparently conserved among fungi, as the homolog of Mga2 in S. pombe was recently identified as oxygen-responsive modulator of lipid homeostasis (Burr et al, 2016).…”

“…Loss of both transcription factors is lethal within a few cell divisions unless UFAs are present in the growth medium, while single deletions are viable even in the absence of exogenous UFAs (Zhang et al, 1997). Homologs of Mga2 and Spt23 have been characterized in the fission yeast Schizosaccharomyces pombe and the pathogenic fungus Candida albicans (Oh and Martin, 2006;Burr et al, 2016). The remarkable sequence conservation of Mga2 and Spt23 among fungi including multiple pathogenic strains, and the absence of an obvious homolog in mammals makes these proteins intriguing drug targets for anti-fungal therapy.…”

CSL protein regulates transcription of genes required to prevent catastrophic mitosis in fission yeast

“…Recently, multiple Cbf11 target genes, including cut6, vht1 and bio2, were shown to be regulated by Mga2, a transcription factor (analogous to mammalian SREBP-1) controlling oxygen-responsive lipid homeostasis in S. pombe. 49 However, it is not yet clear whether or how Cbf11 and Mga2 cooperate to regulate lipid metabolism and/or cellcycle progression. Intriguingly, it has recently been reported that mammalian cells remodel their membrane lipid composition during the cell cycle, and these periodic changes are important for proper cell-cycle progression.…”

The phenomenon of lipid metabolism “cut” mutants

“…The Mga2 transcription factor is important for lipid homeostasis and shares a number of target genes with Cbf11. Also, the degrees of activatory contribution of Mga2 and Cbf11 seem to be similar for many of their shared target genes (Burr et al, ; Převorovský et al, ). Strikingly, no cut phenotype has been reported for the mga2∆ mutant.…”