Regulation of Schizosaccharomyces Pombe Lipid Homeostasis in Response to Low Oxygen by Coordinated Activation of the Transcription Factors Sre1 and Mga2
Authors: Burr Risa , Stewart Emerson V , Shao Wei , Zhao Shan , Hannibal‐Bach Hans Kristian , Ejsing Christer S , Espenshade Peter J 
Published: November 2023

Eukaryotic lipid synthesis is an oxygen‐consumptive process, with cholesterol synthesis requiring 11 oxygen molecules and unsaturated fatty acid synthesis requiring one oxygen molecule per double bond. Therefore lipid homeostasis is dependent on the availability of molecular oxygen. Organisms from yeast to humans monitor and respond to oxygen availability through transcriptional regulation of lipid biosynthesis enzymes. In fission yeast, we previously showed that the Sre1 transcription factor regulates ergosterol homeostasis in response to changing oxygen or sterol levels. Studies in pathogenic fungi have shown that Sre1 homologs are required for adaptation to the low‐oxygen environment of the host and consequently for virulence. We recently identified another transcription factor, Mga2, similarly required for low oxygen adaptation in fission yeast. Microarray and lipidomic analysis established that Mga2 regulates triacylglycerol/glycerophospholipid/unsaturated fatty acid (TAG/GPL/UFA) homeostasis in response to low oxygen (Burr et al, JBC 2016). Both Sre1 and Mga2 are initially in an inactive, ER‐membrane bound state, and upon decrease in oxygen or downstream product availability they are proteolytically activated and released to enter the nucleus and upregulate target genes. Based on their positioning at the head of these two branches of lipid homeostasis, we concluded that Mga2 and Sre1 are the fission yeast analogs of mammalian Sterol Regulatory Element Binding Proteins (SREBP‐1 and SREBP‐2, respectively).

Interestingly, while a shared activation mechanism coordinates mammalian SREBP‐1 and SREBP‐2 activities to maintain homeostasis between sterol and TAG/GPL/UFA biosynthesis, fission yeast Mga2 and Sre1 have different activation mechanisms. Therefore we sought to examine whether and how these two transcriptional programs are coordinated in fission yeast. Indeed, we showed that in the absence of mga2, Sre1 activation is disrupted. Additionally, loss of mga2 or disruption of fatty acid homeostasis by treatment with the fatty acid synthase inhibitor, cerulenin (CER), caused mislocalization of Dsc2 (required for Sre1 activation) and the unrelated Golgi marker Anp1 from the Golgi to the ER and vacuole. Importantly, CER treatment also blocked Sre1 activation in wild‐type cells. Treatment of mga2Δ or CER‐treated cells with UFA rescued Sre1 cleavage and Dsc2/Anp1 localization. These results demonstrate that defects in UFA production perturb membrane function, resulting in mislocalization of Sre1 activation pathway components which is likely responsible for the defect in Sre1 activation in the absence of mga2. Together, this suggests that UFA regulate Sre1 in addition to sterols, providing a unique avenue for coordination of the Mga2 and Sre1 transcriptional programs.

Support or Funding Information

National Institutes of Health Grant HL077588 (to P.J.E.) and VILLUM FONDEN Grant VKR023439 (to C.S.E.)