Put3 Positively Regulates Proline Utilization in Candida albicans

Tebung, Walters Aji; Omran, Raha Parvizi; Fulton, Debra L.; Morschhäuser, Joachim; Whiteway, Malcolm

doi:10.1128/msphere.00354-17

Cited by 19 publications

(35 citation statements)

References 35 publications

(65 reference statements)

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“…The induced levels of Gdh2 expression observed upon phagocytosis is consistent with the apparent low levels of glucose in phagosomes [37]. The induction of Gdh2 expression correlates well with our previous finding that Put2 levels are also induced upon phagocytosis [15], which requires proline binding to the transcription factor Put3 [15,38]. The presence of proline in phagosomes and its metabolism in the mitochondria will generate glutamate.…”

Section: Plos Pathogenssupporting

confidence: 87%

Glutamate dehydrogenase (Gdh2)-dependent alkalization is dispensable for escape from macrophages and virulence of Candida albicans

et al. 2020

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Candida albicans cells depend on the energy derived from amino acid catabolism to induce and sustain hyphal growth inside phagosomes of engulfing macrophages. The concomitant deamination of amino acids is thought to neutralize the acidic microenvironment of phagosomes, a presumed requisite for survival and initiation of hyphal growth. Here, in contrast to an existing model, we show that mitochondrial-localized NAD +-dependent glutamate dehydrogenase (GDH2) catalyzing the deamination of glutamate to α-ketoglutarate, and not the cytosolic urea amidolyase (DUR1,2), accounts for the observed alkalization of media when amino acids are the sole sources of carbon and nitrogen. C. albicans strains lacking GDH2 (gdh2-/-) are viable and do not extrude ammonia on amino acid-based media. Environmental alkalization does not occur under conditions of high glucose (2%), a finding attributable to glucose-repression of GDH2 expression and mitochondrial function. Consistently, inhibition of oxidative phosphorylation or mitochondrial translation by antimycin A or chloramphenicol, respectively, prevents alkalization. GDH2 expression and mitochondrial function are derepressed as glucose levels are lowered from 2% (~110 mM) to 0.2% (~11 mM), or when glycerol is used as primary carbon source. Using time-lapse microscopy, we document that gdh2-/-cells survive, filament and escape from primary murine macrophages at rates indistinguishable from wildtype. In intact hosts, such as in fly and murine models of systemic candidiasis, gdh2-/-mutants are as virulent as wildtype. Thus, although Gdh2 has a critical role in central nitrogen metabolism, Gdh2-catalyzed deamination of glutamate is surprisingly dispensable for escape from macrophages and virulence. Consistently, using the pH-sensitive dye (pHrodo), we observed no significant difference between wildtype and gdh2-/-mutants in phagosomal pH modulation. Following engulfment of fungal cells, the phagosomal compartment is rapidly acidified and hyphal growth initiates and sustained under consistently acidic conditions within phagosomes. Together, our results demonstrate that amino aciddependent alkalization is not essential for hyphal growth, survival in macrophages and

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Section: Plos Pathogenssupporting

confidence: 87%

Glutamate dehydrogenase (Gdh2)-dependent alkalization is dispensable for escape from macrophages and virulence of Candida albicans

et al. 2020

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“…Library preparation and RNA sequencing were carried out at the Quebec Genome Innovation Center located at McGill University using an Illumina MiSeq sequencing platform. RNA-seq data were processed as described previously (31).…”

Section: Methodsmentioning

confidence: 99%

MAP Kinase Regulation of the Candida albicans Pheromone Pathway

Rastghalam

Omran

Alizadeh

et al. 2019

mSphere

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MAP kinases and their regulators are critical components of eukaryotic signaling pathways implicated in normal cell behavior as well as abnormal behaviors linked to diseases such as cancer. The mating pathway of the yeast Saccharomyces cerevisiae was central in establishing the MAP kinase paradigm. Here we investigate the mating pathway in a different ascomycete, the fungal pathogen C. albicans. In this dimorphic fungus MAP kinases are also implicated in the mating response, with two MAP kinases apparently playing redundant roles in the mating process. This work establishes that while some level of mating can occur in the presence of a single kinase, the Cek1 kinase is most important for mating, while the Cek2 kinase is involved in adaptation to signaling. While both kinases appear to be themselves regulated by dephosphorylation through the action of the Cpp1 phosphatase, this process appears important for mating only in the case of Cek1.

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“…The induced levels of Gdh2 expression observed upon phagocytosis is consistent with the apparent low levels of glucose in phagosomes (27). Together with an expected surge in glutamate coming from the catabolism of arginine or proline (15); Put2 levels are upregulated in phagocytized C. albicans , which requires proline binding to the transcription factor Put3 (15, 28). In the presence of arginine as sole nitrogen and carbon source (i.e., YNB+Arg), the role of proline catabolism in alkalization is essential since it is the primary route to generate glutamate in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Glutamate dehydrogenase (Gdh2)-dependent alkalization is dispensable for escape from macrophages and virulence ofCandida albicans

Silao

Ryman

Jiang

et al. 2020

Preprint

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31Candida albicans cells depend on the energy derived from amino acid catabolism to 32 induce and sustain hyphal growth inside phagosomes of engulfing macrophages. 33The concomitant deamination of amino acids is thought to neutralize the acidic 34 microenvironment of phagosomes, a presumed requisite for survival and initiation of 35 hyphal growth. Here, in contrast to an existing model, we show that mitochondrial-36 localized NAD + -dependent glutamate dehydrogenase (GDH2) catalyzing the 37 deamination of glutamate to α-ketoglutarate, and not the cytosolic urea amidolyase 38 (DUR1,2), accounts for the observed alkalization of media when amino acids are the 39 sole sources of carbon and nitrogen. C. albicans strains lacking GDH2 (gdh2-/-) are 40 viable and do not extrude ammonia on amino acid-based media. Environmental 41 alkalization does not occur under conditions of high glucose (2%), a finding 42 attributable to glucose-repression of GDH2 expression and mitochondrial function. 43

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Put3 Positively Regulates Proline Utilization in Candida albicans

Cited by 19 publications

References 35 publications

Glutamate dehydrogenase (Gdh2)-dependent alkalization is dispensable for escape from macrophages and virulence of Candida albicans

Glutamate dehydrogenase (Gdh2)-dependent alkalization is dispensable for escape from macrophages and virulence of Candida albicans

MAP Kinase Regulation of the Candida albicans Pheromone Pathway

Glutamate dehydrogenase (Gdh2)-dependent alkalization is dispensable for escape from macrophages and virulence ofCandida albicans

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