Abstract
Cryptococcus neoformans is an important opportunistic fungal pathogen in humans. Recent studies have demonstrated that metals are critical factors for the regulation of fungal virulence in hosts. In this study, we systemically investigated the function of C. neoformans magnesium transporters in controlling the intracellular Mg balance and virulence‐associated factors. We identified three Mg transporters in C. neoformans: Mgt1, Mgt2, and Mgt3. While we could not detect a Mg2+‐related growth phenotype in mgt1 and mgt3 knockout strains, a GAL7p‐Mgt2 strain showed significant Mg‐dependent growth defects in the presence of glucose. Further analysis demonstrated that MGT2 is a homolog of MNR2 in Saccharomyces cerevisiae, which is localized to the vacuolar membrane and participates in intracellular Mg transport. Interestingly, a transcriptome analysis showed that Mgt2 influenced the expression of 19 genes, which were independent of Mg2+. We showed that melanin synthesis in C. neoformans required Mg2+ and Mgt2, and that capsule production was negatively regulated by Mg2+ and Mgt2. Repressing the expression of MGT2‐induced capsule, which resulted in an increased fungal burden in the lungs. Cumulatively, this study sets the stage for further evaluation of the important role of Mg homeostasis in the regulation of melanin and capsule in C. neoformans.
Highlights
Cryptococcus neoformans is a major fungal pathogen in humans
We demonstrated that a vacuolar Mg2+ transporter (Mgt2) in C. neoformans positively regulated Mg2+ delivery and melanin formation, but negatively controlled capsule production
Fe has been widely accepted as a key regulator of pathogenicity in major human fungal pathogens (Bairwa et al, 2017; Ding et al, 2014; Jung et al, 2006; Lian et al, 2005; Nyhus et al, 1997; Saikia, Oliveira, Hu, & Kronstad, 2014)
Summary
Cryptococcus neoformans is a major fungal pathogen in humans. It primarily afflicts immunodeficient and immunocompetent individuals, causing about 600,000 deaths per year globally (Idnurm et al, 2005; Kronstad et al, 2011; May, Stone, Wiesner, Bicanic, & Nielsen, 2016). Two major fungal virulence factors have been extensively studied These are the generation of a cell-surface polysaccharide capsule structure and melanization using L-DOPA as a substrate (Idnurm et al, 2005; Kronstad et al, 2011). A master Fe homeostasis regulator in C. neoformans, transcription factor Cir was demonstrated to inhibit melanin formation by repressing expression of LAC1 and LAC2. It induces capsule biogenesis by activating capsule production-related genes (Jung et al, 2006). We examined the function of three C. neoformans Mg2+ transporters with respect to the regulation of fungal virulence-associated factors. The mgt mutant displayed an elevated fungal burden in lung tissues as a result of an enlarged capsular structure
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