Mitochondrial proline catabolism activates Ras1/cAMP/PKA-induced filamentation in Candida albicans
| Autor: | Kicki Ryman, Klas I. Udekwu, Björn Brindefalk, Meliza Ward, Axel Wallstrom, Per O. Ljungdahl, Fitz Gerald S. Silao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Arginine
Yeast and Fungal Models Mitochondrion Pathology and Laboratory Medicine Biochemistry chemistry.chemical_compound White Blood Cells Mice Adenosine Triphosphate Animal Cells Gene expression Candida albicans Medicine and Health Sciences Morphogenesis Cyclic AMP Amino Acids Energy-Producing Organelles Candida 2. Zero hunger chemistry.chemical_classification Fungal Pathogens 0303 health sciences biology Virulence Chemistry Organic Compounds Monosaccharides Eukaryota Catabolism Ornithine Cell biology Amino acid Mitochondria Amino acid permease Experimental Organism Systems Medical Microbiology Physical Sciences Pathogens Basic Amino Acids Cellular Structures and Organelles Cellular Types Research Article Signal Transduction Proline lcsh:QH426-470 Immune Cells Immunology Carbohydrates Hyphae Mycology Bioenergetics Research and Analysis Methods Microbiology Fungal Proteins 03 medical and health sciences Proline Oxidase Animals Humans Microbial Pathogens 030304 developmental biology Blood Cells 030306 microbiology Macrophages Organic Chemistry Chemical Compounds Organisms Fungi Biology and Life Sciences Proteins Cyclic Amino Acids Cell Biology biology.organism_classification Cyclic AMP-Dependent Protein Kinases Yeast lcsh:Genetics Glucose Metabolism RAW 264.7 Cells Animal Studies ras Proteins Developmental Biology |
| Zdroj: | PLoS Genetics, Vol 15, Iss 2, p e1007976 (2019) PLoS Genetics |
| DOI: | 10.1101/374777 |
| Popis: | 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. Author summary Candida albicans is an opportunistic fungal pathogen that exists as a benign member of the human microbiome. Immunosuppression, or microbial dysbiosis, can predispose an individual to infection, enabling this fungus to evade innate immune cells and initiate a spectrum of pathologies, including superficial mucocutaneous or even life-threatening invasive infections. Infectious growth is attributed to an array of virulence characteristics, a major one being the ability to switch morphologies from round yeast-like to elongated hyphal cells. Here 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. The finding that proline catabolism, also required for the utilization of arginine and ornithine, is required to sustain the energy demands of hyphal growth underscores the central role of mitochondria in fungal virulence. 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. The results provide a clear example of how C. albicans cells sense and respond to host nutrients to ensure proper nutrient uptake and survival. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|