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dc.contributor.authorSophie Leven_US
dc.contributor.authorDesmarini Desmarinien_US
dc.contributor.authorCecilia Lien_US
dc.contributor.authorMethee Chayakulkeereeen_US
dc.contributor.authorAna Travenen_US
dc.contributor.authorTania C. Sorrellen_US
dc.contributor.authorJulianne T. Djordjevicen_US
dc.contributor.otherUniversity of Sydney Faculty of Medicineen_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherMonash Universityen_US
dc.contributor.otherThe University of Sydneyen_US
dc.date.accessioned2018-10-19T05:04:40Z-
dc.date.available2018-10-19T05:04:40Z-
dc.date.issued2013-04-01en_US
dc.identifier.citationInfection and Immunity. Vol.81, No.4 (2013), 1245-1255en_US
dc.identifier.issn10985522en_US
dc.identifier.issn00199567en_US
dc.identifier.other2-s2.0-84875544623en_US
dc.identifier.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84875544623&origin=inwarden_US
dc.identifier.urihttp://repository.li.mahidol.ac.th/dspace/handle/123456789/31940-
dc.description.abstractPhospholipase C (PLC) of Cryptococcus neoformans (CnPlc1) is crucial for virulence of this fungal pathogen. To investigate the mechanism of CnPlc1-mediated signaling, we established that phosphatidylinositol 4,5-bisphosphate (PIP2) is a major CnPlc1 substrate, which is hydrolyzed to produce inositol trisphosphate (IP3). In Saccharomyces cerevisiae, Plc1-derived IP3 is a substrate for the inositol polyphosphate kinase Arg82, which converts IP3 to more complex inositol polyphosphates. In this study, we show that in C. neoformans, the enzyme encoded by ARG1 is the major IP3 kinase, and we further demonstrate that catalytic activity of Arg1 is essential for cellular homeostasis and virulence in the Galleria mellonella infection model. IP3 content was reduced in the Cnδplc1 mutant and markedly increased in the Cnδarg1 mutant, while PIP2 was increased in both mutants. The Cnδplc1 and Cnδarg1 mutants shared significant phenotypic similarity, including impaired thermotolerance, compromised cell walls, reduced capsule production and melanization, defective cell separation, and the inability to form mating filaments. In contrast to the S. cerevisiae ARG82 deletion mutant (Scδarg82) strain, the Cnδarg1 mutant exhibited dramatically enlarged vacuoles indicative of excessive vacuolar fusion. In mammalian cells, PLC-derived IP3 causes Ca2+release and calcineurin activation. Our data show that, unlike mammalian PLCs, CnPlc1 does not contribute significantly to calcineurin activation. Collectively, our findings provide the first evidence that the inositol polyphosphate anabolic pathway is essential for virulence of C. neoformans and further show that production of IP3 as a precursor for synthesis of more complex inositol polyphosphates is the key biochemical function of CnPlc1. © 2013, American Society for Microbiolog.en_US
dc.rightsMahidol Universityen_US
dc.source.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84875544623&origin=inwarden_US
dc.subjectImmunology and Microbiologyen_US
dc.subjectMedicineen_US
dc.titlePhospholipase C of Cryptococcus neoformans regulates homeostasis and virulence by providing inositol trisphosphate as a substrate for Arg1 kinaseen_US
dc.typeArticleen_US
dc.rights.holderSCOPUSen_US
dc.identifier.doi10.1128/IAI.01421-12en_US
Appears in Collections:Scopus 2011-2015

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