Abstract
To aerobic organisms, low oxygen tension (hypoxia) presents a physiological challenge. To cope with such a challenge, metabolic pathways such as those used in energy production have to be adjusted. Many of such metabolic changes are orchestrated by the conserved hypoxia-inducible factors (HIFs) in higher eukaryotes. However, there are no HIF homologs in fungi or protists, and not much is known about conductors that direct hypoxic adaptation in lower eukaryotes. Here, we discovered that the transcription factor Pas2 controls the transcript levels of metabolic genes and consequently rewires metabolism for hypoxia adaptation in the human fungal pathogen Cryptococcus neoformans Through genetic, proteomic, and biochemical analyses, we demonstrated that Pas2 directly interacts with another transcription factor, Rds2, in regulating cryptococcal hypoxic adaptation. The Pas2/Rds2 complex represents the key transcription regulator of metabolic flexibility. Its regulation of metabolism rewiring between respiration and fermentation is critical to our understanding of the cryptococcal response to low levels of oxygen.IMPORTANCEC. neoformans is the main causative agent of fungal meningitis that is responsible for about 15% of all HIV-related deaths. Although an obligate aerobic fungus, C. neoformans is well adapted to hypoxia conditions that the fungus could encounter in the host or the environment. The sterol regulatory element binding protein (SREBP) is well known for its role in cryptococcal adaptation to hypoxia through its regulation of ergosterol and lipid biosynthesis. The regulation of metabolic reprogramming under hypoxia, however, is largely unknown. Here, we discovered one key regulator, Pas2, that mediates the metabolic response to hypoxia together with another transcription factor, Rds2, in C. neoformans The findings help define the molecular mechanisms underpinning hypoxia adaptation in this and other lower eukaryotes.
Highlights
To aerobic organisms, low oxygen tension presents a physiological challenge
As serotype A and serotype D diverged from a common ancestor 18.5 million years ago [36], the results indicate that the role of Pas2 in regulating hypoxic adaptation is conserved in the Cryptococcus neoformans species complex
Genes involved in glycolysis and fermentation were highly induced, while some mitochondrial genes related to OXOPHOS were downregulated (Fig. 1; see Data Set S1 in the supplemental material)
Summary
Low oxygen tension (hypoxia) presents a physiological challenge. We discovered one key regulator, Pas, that mediates the metabolic response to hypoxia together with another transcription factor, Rds, in C. neoformans. HIFs promote pyruvate reduction to lactate by activating lactate dehydrogenase A (LDHA) [6] These changes shunt pyruvate away from mitochondrial oxidation and regenerate NAD1 to permit continued glycolysis and, continued ATP production under hypoxia. In the obligate aerobic mold Aspergillus nidulans, exposure to hypoxia results in an increase in the transcript levels of genes involved in glycolysis, fermentation, and the g-aminobutyrate (GABA) shunt, which bypasses two steps of the tricarboxylic acid (TCA) cycle [11]. Transcriptomic and proteomic studies in a related species, Aspergillus fumigatus, under hypoxia revealed increases in the oxidative stress response, glycolysis and fermentation, cell wall biosynthesis, and iron metabolism with concomitant decreases in the TCA cycle [12]. No homologs of HIFs have been identified in lower eukaryotes that regulate the metabolic response to hypoxia
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