The Vacuolar Ca ²⁺ ATPase Pump Pmc1p Is Required for Candida albicans Pathogenesis

Abstract

Maintenance of Ca2+ homeostasis is important for fungal cells to respond to a multitude of stresses, as well as antifungal treatment, and for virulence in animal models. Here, we demonstrate that a P-type ATPase, Pmc1p, is required for Candida albicans to respond to a variety of stresses, affects azole susceptibility, and is required to sustain tissue invasive hyphal growth and to cause disease in a mouse model of disseminated infection. Defining the mechanisms responsible for maintaining proper Ca2+ homeostasis in this important human pathogen can ultimately provide opportunities to devise new chemotherapeutic interventions that dysregulate intracellular signaling and induce Ca2+ toxicity.

Synergistic Effect of Berberine Hydrochloride and Fluconazole Against Candida albicans Resistant Isolates

“…Constitutive efflux pump upregulation, including CDR1, CDR2, and MDR1, is a key contributor to early biofilm resistance in C. albicans ( Nobile and Johnson, 2015 ). Luna-Tapia et al (2019) demonstrated that the calcium pump Pmc1p is essential for transformation from yeast-to-hyphae and biofilm formation. Previous work indicated that the vacuolar calcium channel Yvc1p participates in hyphal elongation and maintenance by regulating hyphal-associated gene expression ( Yu et al, 2014 ).…”

“…In our study, both FLC monotherapy and BBH + FLC downregulated VCX1 and PMR1 , but there was no statistical difference. Luna-Tapia et al (2019) reported that pmc1Δ/Δ mutants are severely impaired by high Ca 2+ concentration in the medium, because they are unable to transport Ca 2+ from the cytoplasm into the vacuole. However, vcx1Δ/Δ mutants are unaffected by high Ca 2+ , demonstrating that Pmc1p is required for C. albicans pathogenicity, FLC tolerance, and hyphal growth ( Luna-Tapia et al, 2019 ).…”

“… Luna-Tapia et al (2019) reported that pmc1Δ/Δ mutants are severely impaired by high Ca 2+ concentration in the medium, because they are unable to transport Ca 2+ from the cytoplasm into the vacuole. However, vcx1Δ/Δ mutants are unaffected by high Ca 2+ , demonstrating that Pmc1p is required for C. albicans pathogenicity, FLC tolerance, and hyphal growth ( Luna-Tapia et al, 2019 ). Thus, YVC1 and PMC1 might be the most important calcium-related genes to maintain cellular calcium homeostasis in FLC-resistant C. albicans , and may be antifungal therapy targets.…”

“…One limitation of this study is that additional synergistic regulatory sites need to be further explored. Hyphae are a key factor for C. albicans virulence and invasiveness, and some researchers observed that Ca 2+ -regulated genes YVC1 and PMC1 deletion cause hyphae defects in C. albicans ( Yu et al, 2014 ; Luna-Tapia et al, 2019 ). We found that combined BBH + FLC simultaneously regulates vacuolar Ca 2+ -regulated genes and significantly inhibits yeast-to-hyphae conversion.…”

Calcineurin Regulates Conidiation, Chlamydospore Formation and Virulence in Fusarium oxysporum f. sp. lycopersici

“…Previous studies in Candida spp. demonstrated that the expression of PMC1 was regulated by calcineurin (Sanglard et al, 2003;Chen et al, 2011), and was required for pathogenesis in C. albicans (Luna-Tapia et al, 2019). The pmcA (PMC1 ortholog) mutant in A. fumigatus was found to be avirulent (Dinamarco et al, 2012).…”