The putative vacuolar ATPase subunit Vma7p of Candida albicans is involved in vacuole acidification, hyphal development and virulence

Abstract

The vacuolar H + -ATPase (V-ATPase) component Vma7p of the human-pathogenic yeast Candida albicans regulates hyphal growth induced by serum and Spider medium and is essential for virulence. In order to characterize the functions of the putative V-ATPase subunit Vma7p of C. albicans, null mutants were generated. The resulting mutants showed reduced vacuole acidification, which correlated with defective growth at alkaline pH. In addition, defects in degradation of intravacuolar putative endosomal structures were observed. vma7 null mutants were sensitive towards the presence of metal ions. It is concluded that the sequestration of toxic ions in the vacuole via a H + gradient generated by the V-ATPase is affected. The vma7 null mutant strains were avirulent in a mouse model of systemic candidiasis. In addition, C. albicans vma7 null mutants and the null mutant strain of the Vma7p-interacting phosphatidylinositol 3-kinase Vps34p showed similar phenotypes. In summary, the V-ATPase subunit Vma7p is involved in vacuolar ion transport and this transport is required for hyphal growth and virulence of C. albicans.

The Contribution of Candida albicans Vacuolar ATPase Subunit V 1 B, Encoded by VMA2 , to Stress Response, Autophagy, and Virulence Is Independent of Environmental pH

“…The contribution of several V-ATPase subunits to C. albicans cell biology and virulence has been studied previously (3,4,12,13). Here, we present the study of C. albicans VMA2, which encodes the B subunit of the V-ATPase V 1 domain; this is the first component of the catalytic hexamer of the V 1 complex to be studied in depth in C. albicans.…”

“…V-ATPase inhibition also interferes with virulence-related traits in C. albicans, including the secretion of degradative enzymes and yeast-to-hypha transitioning (3,4,12,13). Notably, V-ATPase previously has been shown to be important for in vivo virulence in C. albicans (3,13); however, the requirement of acidic environmental pH for the growth of VATPase mutants complicates the interpretation of these studies due to the growth-limiting alkaline pH in the bloodstream of the murine host.…”

“…The acidification of these organelles has several important functions: first, the protons pumped into the compartment by V-ATPase energize multiple secondary transporter systems, such as those involved in metal ion homeostasis, and second, the acidic pH created by V-ATPase is necessary for the activity of degradative enzymes. Accordingly, in both Saccharomyces cerevisiae and C. albicans, mutations in VATPase lead to the Vma Ϫ phenotype, which is characterized by poor growth at alkaline pH as well as defective metal sequestration, glycerol metabolism, and other responses to environmental stress conditions (1,(3)(4)(5)(6). V-ATPase mutants are also impaired in vacuolar biogenesis due to defects in both vacuolar membrane fusion and fission (7).…”

“…In addition to its requirement for intraorganellar pH homeostasis, V-ATPase function has been implicated in cytosolic and extracellular pH homeostasis (1,(8)(9)(10)(11), underscoring the far-reaching importance of this pump to overall cellular homeostasis. V-ATPase inhibition also interferes with virulence-related traits in C. albicans, including the secretion of degradative enzymes and yeast-to-hypha transitioning (3,4,12,13). Notably, V-ATPase previously has been shown to be important for in vivo virulence in C. albicans (3, 13); however, the requirement of acidic environmental pH for the growth of VATPase mutants complicates the interpretation of these studies due to the growth-limiting alkaline pH in the bloodstream of the murine host.…”

The Where, When, and How of Organelle Acidification by the Yeast Vacuolar H + -ATPase

“…Other fungi, including Neurospora crassa, Candida albicans, and Schizosaccharomyces pombe, also show a pH-dependent growth phenotype upon disruption of V-ATPase subunits (10,56,119), but disruption of V-ATPase function in higher eukaryotes is lethal (15,108,142). The exception to this is mutations in tissue-specific isoforms of certain subunits in mammalian cells.…”