REGULATION OF LIPID HOMEOSTASIS DURING LOW OXYGEN ADAPTATION IN SCHIZOSACCHAROMYCES POMBE

Adaptation to environmental change is a hallmark of life, and fundamental factors including oxygen, lipids, nutrients, pH, and temperature are in a constant state of flux in many cellular environments. All organisms, from single-celled yeast to multicellular humans, must sense and adapt to these changing environmental conditions in order to survive and reproduce. This sensing and response is often regulated on the level of transcription factors, so that a broad set of genes can be altered in concert through changes in a single or small number of sensors. Due to the essential nature of these adaptations, the relevant transcription factor pathways are often conserved across species and can be highly complex in order to precisely tune the response. Therefore, study of these transcription factor pathways in the non-pathogenic fungus Schizosaccharomyces pombe may establish universal paradigms that are broadly applicable to other fungal species or to eukaryotes in general. In this thesis, I defined a novel role for the AAA+ ATPase Cdc48 and its cofactor Ufd1 in the Golgi localization of the Dsc E3 ligase complex. This role ultimately impinges on cleavage of the SREBP transcription factor responsible for regulation of sterol biosynthesis in response to low oxygen in fission yeast. Through that work I also generated the first list of Cdc48 binding proteins in S. pombe, which can be used in the future to identify new Cdc48 cofactors and pathways that may be important to other cellular processes. I also uncovered a new regulator of the low oxygen response - Mga2. I demonstrated that Mga2 transcriptionally regulates phospholipid biosynthesis in response to low oxygen, acting alongside SREBPs to regulate lipid homeostasis. Further, I showed evidence of potential coordination of SREBP and Mga2 activation, suggesting broader co-regulation of these two pathways to keep overall lipid homeostasis in balance. In the future, I hope these insights will lead to establishment of Mga2 as important for low oxygen adaptation in pathogenic fungi