Virulence of the Fungal Pathogen
            <i>Candida albicans</i>
            Requires the Five Isoforms of Protein Mannosyltransferases

Rouabhia, Mahmoud; Schaller, Martin; Corbucci, Cristina; Vecchiarelli, Anna; Prill, Stephan K.-H.; Giasson, Luc; Ernst, Joachim F.

doi:10.1128/iai.73.8.4571-4580.2005

Cited by 85 publications

(84 citation statements)

References 38 publications

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“…Although additional Northern analysis revealed that PMT1 and PMT2 are also expressed under these conditions (data not shown), PMT2 was predicted to be essential based on studies of other microorganisms, and we also predicted that Pmt1 and Pmt2 likely function together as a heterodimer. In other fungi, Pmt4 enzymatic activity is important for cell wall formation, cell integrity, and pathogenesis but is not essential for viability (34,46). Therefore, for initial gene disruption experiments, we chose to study the PMT4 gene to assess the role of Pmt-mediated O mannosylation in C. neoformans growth and pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…pmt4/pmt4 homozygous mutants are significantly attenuated in mouse models of hematogenously disseminated candidiasis (34). In our studies, we used two murine models of cryptococcal disease, intravenous and inhalation, to examine the role of Pmt4 in C. neoformans pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Mannosylated proteins are predominant immunogens of this opportunistic fungal pathogen (19). Also, defective protein O mannosylation is known to result in morphological defects in other fungi, and subtle morphological changes have been associated with considerable alterations in fungal survival in vivo (3,34). Here we have identified three Pmt homologues in C. neoformans and examined the role of one such Pmt homologue, designated Pmt4, in cell integrity, cell separation, and pathogenesis.…”

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confidence: 99%

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Role of Protein O -Mannosyltransferase Pmt4 in the Morphogenesis and Virulence of Cryptococcus neoformans

et al. 2007

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Protein O mannosylation is initiated in the endoplasmic reticulum by protein O-mannosyltransferases (Pmt proteins) and plays an important role in the secretion, localization, and function of many proteins, as well as in cell wall integrity and morphogenesis in fungi. Three Pmt proteins, each belonging to one of the three respective Pmt subfamilies, are encoded in the genome of the human fungal pathogen Cryptococcus neoformans. Disruption of the C. neoformans PMT4 gene resulted in abnormal growth morphology and defective cell separation. Transmission electron microscopy revealed defective cell wall septum degradation during motherdaughter cell separation in the pmt4 mutant compared to wild-type cells. The pmt4 mutant also demonstrated sensitivity to elevated temperature, sodium dodecyl sulfate, and amphotericin B, suggesting cell wall defects. Further analysis of cell wall protein composition revealed a cell wall proteome defect in the pmt4 mutant, as well as a global decrease in protein mannosylation. Heterologous expression of C. neoformans PMT4 in a Saccharomyces cerevisiae pmt1pmt4 mutant strain functionally complemented the deficient Pmt activity. Furthermore, Pmt4 activity in C. neoformans was required for full virulence in two murine models of disseminated cryptococcal infection. Taken together, these results indicate a central role for Pmt4-mediated protein O mannosylation in growth, cell wall integrity, and virulence of C. neoformans.Protein O glycosylation is a fundamentally important protein modification in eukaryotes, in which glycosyl residues are covalently attached to secreted proteins. In fungi, O glycosylation is often referred to as O mannosylation. In the yeast Saccharomyces cerevisiae, protein O mannosylation is essential for cell viability, cell wall formation, cell integrity, morphology, and budding, and the secretion, localization, and function of many proteins (6,22,35,36). In the human fungal pathogen, Candida albicans, O mannosylation is involved in morphogenic transitions and virulence (16,23). Furthermore, decreased O mannosylation of proteins in these fungi also results in cell wall changes leading to increased sensitivity to certain antifungal compounds and cell wall destabilizing agents (25,32,38,39).Protein O mannosylation is initiated in the endoplasmic reticulum by protein O-mannosyltransferases (Pmts) that catalyze the transfer of mannose from the sugar donor, dolichol phosphate-mannose, to the hydroxyl groups of serine and threonine residues in the secreted acceptor protein. The Pmt enzymes have been extensively studied in S. cerevisiae, for which seven Pmt proteins have been described previously (37). Recently, five Pmts were described for C. albicans and three for the fission yeast Schizosaccharomyces pombe (32,46). Two PMT genes in S. pombe, OMA1 and OMA4, are not essential for viability. However, oma1⌬ and oma4⌬ mutants exhibit abnormal cell morphology, altered cell wall structure, and partial cell separation defects (46). The third S. pombe PMT gene,

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Role of Protein O -Mannosyltransferase Pmt4 in the Morphogenesis and Virulence of Cryptococcus neoformans

et al. 2007

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“…The deletion of pmt4 is associated with a drastic reduction in appressorium formation and, more importantly, those appressoria that do form are nonfunctional in terms of plant penetration. Thus, protein O-mannosylation can now be considered a protein modification process essential for U. maydis virulence and, as PMT family proteins are not conserved in plants (Rouabhia et al, 2005;Bowman and Free, 2006), they may represent an interesting target for future antifungal drugs.…”

Section: Discussionmentioning

confidence: 99%

TheO-Mannosyltransferase PMT4 Is Essential for Normal Appressorium Formation and Penetration inUstilago maydis

2009

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In Saccharomyces cerevisiae, the PMT, KRE2/MNT1, and MNN1 mannosyltransferase protein families catalyze the steps of the O-mannosylation pathway, sequentially adding mannoses to target proteins. We have identified members of all three families and analyzed their roles in pathogenesis of the maize smut fungus Ustilago maydis. Furthermore, we have shown that PMT4, one of the three PMT family members in U. maydis, is essential for tumor formation in Zea mays. Significantly, PMT4 seems to be required only for pathogenesis and is dispensable for other aspects of the U. maydis life cycle. We subsequently show that the deletion of pmt4 results in a strong reduction in the frequency of appressorium formation, with the few appressoria that do form lacking the capacity to penetrate the plant cuticle. Our findings suggest that the O-mannosylation pathway plays a key role in the posttranslational modification of proteins involved in the pathogenic development of U. maydis. The fact that PMT homologs are not found in plants may open new avenues for the development of fungal control strategies. Moreover, the discovery of a highly specific requirement for a single O-mannosyltransferase should aid in the identification of the proteins directly involved in fungal plant penetration, thus leading to a better understanding of plant-fungi interactions.

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“…Mannan synthesis is regulated by several specific glycosyl transferases. [15][16][17] It is also an immunochemical determinant of Candida spp. 18,19) It is of note that the structure of mannan is modulated by various culture conditions, such as temperature and pH.…”

Section: 6)mentioning

confidence: 99%

Beta-Mannosyl Linkages Negatively Regulate Anaphylaxis and Vasculitis in Mice, Induced by CAWS, Fungal PAMPs Composed of Mannoprotein-Beta-Glucan Complex Secreted by Candida albicans

Shinohara

Nagi-Miura

Ishibashi

et al. 2006

Biological & Pharmaceutical Bulletin

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Virulence of the Fungal Pathogen Candida albicans Requires the Five Isoforms of Protein Mannosyltransferases

Cited by 85 publications

References 38 publications

Role of Protein O -Mannosyltransferase Pmt4 in the Morphogenesis and Virulence of Cryptococcus neoformans

Role of Protein O -Mannosyltransferase Pmt4 in the Morphogenesis and Virulence of Cryptococcus neoformans

TheO-Mannosyltransferase PMT4 Is Essential for Normal Appressorium Formation and Penetration inUstilago maydis

Beta-Mannosyl Linkages Negatively Regulate Anaphylaxis and Vasculitis in Mice, Induced by CAWS, Fungal PAMPs Composed of Mannoprotein-Beta-Glucan Complex Secreted by Candida albicans

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