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Rai, M.N. and Sharma, V. and Balusu, S. and Kaur, Rupinder (2015) An essential role for phosphatidylinositol 3-kinase in the inhibition of phagosomal maturation, intracellular survival and virulence inCandida glabrata. Cellular Microbiology, 17 (2). pp. 269-287. ISSN 1462-5814

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The yeast class III phosphoinositide 3-kinase (PI3K) that catalyses production of the lipid signalling molecule, phosphatidylinositol-3-phosphate, is primarily implicated in vesicle-mediated transport and autophagy. In this study, we identified, through a genetic screen, the Candida glabrata CgVPS15 gene, an orthologue of the Saccharomyces cerevisiae PI3K regulatory subunit-encoding open reading frame (ORF) to be required for impairment of phagosomal maturation in human macrophages. We also disrupted catalytic subunit of the C. glabrata PI3K complex, CgVps34, and found it to be pivotal to arrest mature phagolysosome biogenesis. Further, deletion of either CgVPS15 or CgVPS34 rendered C. glabrata cells hyperadherent to epithelial cells and susceptible to the antimicrobial arsenal of primary murine and cultured human macrophages and diverse stresses. Despite no growth retardation at 37°C, Cgvps15Δ and Cgvps34Δ mutants were severely virulence attenuated in mice. We demonstrate that trafficking and/or processing of the vacuolar lumenal hydrolase, carboxypeptidase Y, and the major adhesin, Epa1, rely on PI3K regulatory mechanisms in C. glabrata. By disrupting autophagy-related PI3K complex genes, we show that C. glabrata PI3K-impeded phagolysosomal acidification is primarily owing to its role in cellular trafficking events. Altogether, our findings underscore the essentiality of PI3K signalling in modulation of host immune response, intracellular survival and virulence in C. glabrata. Copyright © 2014 John Wiley & Sons Ltd

Item Type: Article
Depositing User: Dr P Divakar
Date Deposited: 17 May 2015 19:18
Last Modified: 24 Sep 2015 05:57
URI: http://cdfd.sciencecentral.in/id/eprint/46

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