The Hog1 Mitogen-Activated Protein Kinase Mediates a Hypoxic Response inSaccharomyces cerevisiae

Abstract

We have studied hypoxic induction of transcription by studying the seripauperin (PAU ) genes of Saccharomyces cerevisiae. Previous studies showed that PAU induction requires the depletion of heme and is dependent upon the transcription factor Upc2. We have now identified additional factors required for PAU induction during hypoxia, including Hog1, a mitogen-activated protein kinase (MAPK) whose signaling pathway originates at the membrane. Our results have led to a model in which heme and ergosterol depletion alters membrane fluidity, thereby activating Hog1 for hypoxic induction. Hypoxic activation of Hog1 is distinct from its previously characterized response to osmotic stress, as the two conditions cause different transcriptional consequences. Furthermore, Hog1-dependent hypoxic activation is independent of the S. cerevisiae general stress response. In addition to Hog1, specific components of the SAGA coactivator complex, including Spt20 and Sgf73, are also required for PAU induction. Interestingly, the mammalian ortholog of Spt20, p38IP, has been previously shown to interact with the mammalian ortholog of Hog1, p38. Taken together, our results have uncovered a previously unknown hypoxic-response pathway that may be conserved throughout eukaryotes.

Yeast Saccharomyces cerevisiae adiponectin receptor homolog Izh2 is involved in the regulation of zinc, phospholipid and pH homeostasis

“…It is notable in this respect that lipid metabolism is strongly regulated at the epigenetic level 79 , which is, through Zn-dependent HDACs, heavily dependent on zinc concentration. A similar hierarchy of shared control between regulators has been proposed before, for instance in membrane alterations caused by ergosterol and heme depletion 80 . While Hog1 has been the multifunctional protein shown in that study to confer cellular adaptation, it is interesting that Izh2 has been linked with both ergosterol metabolism and cellular response to hypoxia 16,55 .…”

Repurposing of Aspirin and Ibuprofen as Candidate Anti-Cryptococcus Drugs

“…Bahn et al reported that the phosphorylation of Hog1 MAPK activates downstream target genes to effect adaptation to environmental stressors (24). The Hog1 signaling pathway is, interestingly, also reported to be responsible for the maintenance of cell membrane/wall integrity (13,14). Thus, in our study, we sought to establish if the treatment of cells with aspirin and ibuprofen can cause membrane damage and, in turn, lead to activation of Hog1 MAPK.…”

“…In order to determine if our two test drugs could lead to stress induction, we performed a Hog1 mitogen-activated protein kinase (MAPK) Western blot assay (13,14) that was complemented with a phospho-p38 MAPK enzyme-linked immunosorbent assay (ELISA). For Western blot analysis, cultures were treated with 180 g/ml aspirin, 206 g/ml ibuprofen, 58,000 g/ml (1 M) sodium chloride (NaCl; Sigma-Aldrich, South Africa), or 34 g/ml (1 mM) hydrogen peroxide (H 2 O 2 ; Sigma-Aldrich, South Africa) for 20 min (grown at 30°C in YNB broth).…”

Osmoregulation in Saccharomyces cerevisiae via mechanisms other than the high-osmolarity glycerol pathway

“…Similar results were obtained by comparing osmotolerant anaerobic strains to GPD1 overexpressing strains. Interestingly, Hickman et al (2011) also reported hypoxia-mediated activation of Hog1p and demonstrated that kinetics of Hog1p activation in response to hypoxia and osmotic stress are very different. Hog1p shows rapid transient activation in response to osmotic stress response as reported earlier, but it is activated slowly (over a period of 5 h) in response to hypoxia (Hickman et al, 2011).…”