The Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis
ABSTRACT Calcium is a critically important secondary messenger of intracellular signal transduction in eukaryotes but must be maintained at low levels in the cytoplasm of resting cells to avoid toxicity. This is achieved by several pumps that actively transport excess cytoplasmic Ca2+ out of the cel...
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American Society for Microbiology
2019
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oai:doaj.org-article:6096f121cb3f41459643d166be2241b72021-11-15T15:22:04ZThe Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis10.1128/mSphere.00715-182379-5042https://doaj.org/article/6096f121cb3f41459643d166be2241b72019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00715-18https://doaj.org/toc/2379-5042ABSTRACT Calcium is a critically important secondary messenger of intracellular signal transduction in eukaryotes but must be maintained at low levels in the cytoplasm of resting cells to avoid toxicity. This is achieved by several pumps that actively transport excess cytoplasmic Ca2+ out of the cell across the plasma membrane and into other intracellular compartments. In fungi, the vacuole serves as the major storage site for excess Ca2+, with two systems actively transporting cytoplasmic calcium ions into the vacuole. The H+/Ca2+ exchanger, Vcx1p, harnesses the proton-motive force across the vacuolar membrane (generated by the V-ATPase) to drive Ca2+ transport, while the P-type ATPase Pmc1p uses ATP hydrolysis to translocate Ca2+ into the vacuole. Ca2+-dependent signaling is required for the prevalent human fungal pathogen Candida albicans to endure exposure to the azole antifungals and to cause disease within the mammalian host. The purpose of this study was to determine if the Pmc1p or Vcx1p Ca2+ pumps are required for C. albicans pathogenicity and if these pumps impact antifungal resistance. Our results indicate that Pmc1p is required by C. albicans to transition from yeast to hyphal growth, to form biofilms in vitro, and to cause disease in a mouse model of disseminated infection. Moreover, loss of Pmc1p function appears to enhance C. albicans azole tolerance in a temperature-dependent manner. IMPORTANCE 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.Arturo Luna-TapiaChristian DeJarnetteEmily SansevereParker ReitlerArielle ButtsKirk E. HevenerGlen E. PalmerAmerican Society for MicrobiologyarticleCandida albicansPmc1pVcx1pcalciumpathogenesisvacuoleMicrobiologyQR1-502ENmSphere, Vol 4, Iss 1 (2019) |
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DOAJ |
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EN |
| topic |
Candida albicans Pmc1p Vcx1p calcium pathogenesis vacuole Microbiology QR1-502 |
| spellingShingle |
Candida albicans Pmc1p Vcx1p calcium pathogenesis vacuole Microbiology QR1-502 Arturo Luna-Tapia Christian DeJarnette Emily Sansevere Parker Reitler Arielle Butts Kirk E. Hevener Glen E. Palmer The Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis |
| description |
ABSTRACT Calcium is a critically important secondary messenger of intracellular signal transduction in eukaryotes but must be maintained at low levels in the cytoplasm of resting cells to avoid toxicity. This is achieved by several pumps that actively transport excess cytoplasmic Ca2+ out of the cell across the plasma membrane and into other intracellular compartments. In fungi, the vacuole serves as the major storage site for excess Ca2+, with two systems actively transporting cytoplasmic calcium ions into the vacuole. The H+/Ca2+ exchanger, Vcx1p, harnesses the proton-motive force across the vacuolar membrane (generated by the V-ATPase) to drive Ca2+ transport, while the P-type ATPase Pmc1p uses ATP hydrolysis to translocate Ca2+ into the vacuole. Ca2+-dependent signaling is required for the prevalent human fungal pathogen Candida albicans to endure exposure to the azole antifungals and to cause disease within the mammalian host. The purpose of this study was to determine if the Pmc1p or Vcx1p Ca2+ pumps are required for C. albicans pathogenicity and if these pumps impact antifungal resistance. Our results indicate that Pmc1p is required by C. albicans to transition from yeast to hyphal growth, to form biofilms in vitro, and to cause disease in a mouse model of disseminated infection. Moreover, loss of Pmc1p function appears to enhance C. albicans azole tolerance in a temperature-dependent manner. IMPORTANCE 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. |
| format |
article |
| author |
Arturo Luna-Tapia Christian DeJarnette Emily Sansevere Parker Reitler Arielle Butts Kirk E. Hevener Glen E. Palmer |
| author_facet |
Arturo Luna-Tapia Christian DeJarnette Emily Sansevere Parker Reitler Arielle Butts Kirk E. Hevener Glen E. Palmer |
| author_sort |
Arturo Luna-Tapia |
| title |
The Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis |
| title_short |
The Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis |
| title_full |
The Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis |
| title_fullStr |
The Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis |
| title_full_unstemmed |
The Vacuolar Ca<sup>2+</sup> ATPase Pump Pmc1p Is Required for <named-content content-type="genus-species">Candida albicans</named-content> Pathogenesis |
| title_sort |
vacuolar ca<sup>2+</sup> atpase pump pmc1p is required for <named-content content-type="genus-species">candida albicans</named-content> pathogenesis |
| publisher |
American Society for Microbiology |
| publishDate |
2019 |
| url |
https://doaj.org/article/6096f121cb3f41459643d166be2241b7 |
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