Abstract
Amino acids are among the earliest identified inducers of yeast-to-hyphal transitions in Candida albicans, an opportunistic fungal pathogen of humans. Here, we show that the morphogenic amino acids arginine, ornithine and proline are internalized and metabolized in mitochondria via a PUT1- and PUT2-dependent pathway that results in enhanced ATP production. Elevated ATP levels correlate with Ras1/cAMP/PKA pathway activation and Efg1-induced gene expression. The magnitude of amino acid-induced filamentation is linked to glucose availability; high levels of glucose repress mitochondrial function thereby dampening filamentation. Furthermore, arginine-induced morphogenesis occurs more rapidly and independently of Dur1,2-catalyzed urea degradation, indicating that mitochondrial-generated ATP, not CO2, is the primary morphogenic signal derived from arginine metabolism. The important role of the SPS-sensor of extracellular amino acids in morphogenesis is the consequence of induced amino acid permease gene expression, i.e., SPS-sensor activation enhances the capacity of cells to take up morphogenic amino acids, a requisite for their catabolism. C. albicans cells engulfed by murine macrophages filament, resulting in macrophage lysis. Phagocytosed put1-/- and put2-/- cells do not filament and exhibit reduced viability, consistent with a critical role of mitochondrial proline metabolism in virulence.
Highlights
Candida albicans is an opportunistic fungal pathogen that exists as a benign member of the human microbiome
We report that mitochondrial proline catabolism is required to induce hyphal growth of C. albicans cells in phagosomes of engulfing macrophages, which is key to evade killing by macrophages
In contrast to existing dogma, we show that in C. albicans, mitochondrial function is subject to glucose repression, amino acid-induced signals are strictly dependent on Ras1 and the SPS-sensor is the primary sensor of extracellular amino acids
Summary
Candida albicans is an opportunistic fungal pathogen that commonly exists as a benign member of the human microbiome. C. albicans can asymptomatically colonize virtually all anatomical sites in the host, each with a characteristic and unique microenvironment, with differing nutrient and microbiome compositions, physical properties, and levels of innate immune defenses [3]. C. albicans can assume at least three distinct morphologies: yeast-like, pseudohyphae, and true hyphae, where the latter two are commonly referred to as filamentous morphologies (for review see [4,5,6,7]). Strains that are genetically locked in either yeast or filamentous forms fail to mount infections in vitro and in vivo infection models, supporting the concept that morphological switching, rather than the specific morphology per se, is a requisite to virulence [4, 6, 8,9,10]. The environmental signals known to trigger morphogenesis in C. albicans reflect the conditions within the human host, such as temperature (37 ̊C), CO2, alkaline pH, the presence of serum, N-acetylglucosamine, and a discrete set of amino acids
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