Phosphatidylinositol 3-kinase VPS34 of is involved in filamentous growth, secretion of aspartic proteases, and intracellular detoxification

Abstract

The phosphatidylinositol (PI) 3-kinase Vps34p of Candida albicans influences vesicular intracellular transport, filamentous growth and virulence. To get a clearer understanding how these phenomena are connected, we analysed hyphal growth in a matrix under microaerophilic conditions at low temperature, the detoxification of metal ions and antifungal drugs, the secretion of aspartic proteinases (Saps), as well as expression of adhesion-associated proteins of the C. albicans vps34 null mutant strain. The hyphal growth in a matrix, which is repressed in the wild-type strain by Efg1p, was derepressed in the mutant. CZF1, which encodes an activator of hyphal growth in a matrix, was up-regulated in the mutant. In addition, CZF1 expression was pH-dependent in the wild-type. Expression of EFG1 was not changed. Examination of Saps secretion showed a reduction in the vps34 null mutant. Determination of sensitivity against metal ions and antimycotic drugs revealed defects in detoxification. Expression studies indicated that the vps34 mutant reacts to the phenotypical defects with an up-regulation of genes involved in these processes, including the aspartyl proteinases SAP2 and SAP9, adhesion proteins ALS1 and HWP1, and the ABC transporters CDR1 and HST6. We also found an increased expression of the PI 4-kinase LSB6 indicating a complex feed-back mechanism for the compensation of the multiple defects arising from the lack of the PI3-kinase VPS34.

PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans

“…However, the present studies indicate that PI3K-dependent induction of autophagy is also a tool used by the eukaryotic pathogen to ensure survival and effect host cell damage. Interestingly, the fungal pathogen Candida albicans has not been found to be dependent on autophagy for virulence (41), although a reduction in virulence was found by deletion of a vps34Δ homolog (42), which may suggest that the 2 pathogens encounter different host-cell environments leading to varied requirements for an autophagic response. Alternatively, this could be a reflection of pathogen-specific alterations in the host cell environment.…”

Candida albicans VPS1 contributes to protease secretion, filamentation, and biofilm formation

“…Deletion of the VPS11 gene results in a strain that is deficient in secretion of Saps and lipases (Palmer et al, 2003). The class E type of vacuolar mutants vps34Δ and vps4Δ are also unable to secrete Sap2 protein in C. albicans (Kitanovic et al, 2005;Lee et al, 2007). Interestingly, the C. albicans vps4Δ null mutant secretes an increased amount of extracellular proteolytic activity on BSA plates, which has been identified as missorted carboxypeptidase.…”

“…C. albicans vps28Δ and vps34Δ null mutants exhibit defects in filamentation that are dependent on the RIM101 pathway (Cornet et al, 2005). The C. albicans vps34Δ null mutant produces more hyphae than the wild-type control when embedded in solid agar matrix at 23 °C (Kitanovic et al, 2005), but when grown in liquid hyphae-inducing medium at 37 °C , filamentation is considerably delayed in the mutant strain (Bruckmann et al, 2000). The C. albicans vps11Δ null mutant is unable to produce filaments and it has been suggested that VPS11 may play a role in vacuolar expansion required for yeast to hyphal morphogenesis (Palmer et al, 2003;Palmer et al, 2005).…”

Environmental Sensing and Signal Transduction Pathways Regulating Morphopathogenic Determinants of Candida albicans

“…Overexpression of CZF1 stimulates filamentous growth but only under embedded conditions and in certain media lacking glucose. The expression of Czf1 is strongly up-regulated in a vps34 mutant; as a result, a vps34 mutant is derepressed in hyphal formation under microaerophilic conditions (150). Vps34 is phosphatidylinositol-3-kinase, which influences vesicular intracellular transport, filamentous growth, and virulence.…”