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Ofir A.,Technion IIT and the Rappaport Institute for Research in the Medical science | Hofmann K.,University of Cologne | Weindling E.,Technion IIT and the Rappaport Institute for Research in the Medical science | Gildor T.,Technion IIT and the Rappaport Institute for Research in the Medical science | And 3 more authors.
Molecular Microbiology | Year: 2012

To explore cell cycle regulation in the dimorphic fungus Candida albicans, we identified and characterized CaNrm1, a C.albicans homologue of the Saccharomyces cerevisiae Whi5 and Nrm1 transcription inhibitors that, analogous to mammalian Rb, regulate the cell cycle transcription programme during the G1 phase. CaNRM1 is able to complement the phenotypes of both whi5 and nrm1 mutants in S.cerevisiae. In C.albicans, global transcription analysis of the CaNRM1 deletion mutant reveals a preferential induction of G1- and G1/S-specific genes. CaNrm1 interacts genetically with the C.albicans MBF functional homologue, and physically with its subunit CaSwi4. Similar to S.cerevisiae Whi5, CaNrm1 subcellular localization oscillates with the cell cycle between the nucleus and the cytoplasm. Deletion of CaNRM1 further results in increased resistance to hydroxyurea, an inhibitor of DNA replication; analysis of the expression of ribonucleotide reductase, the target of hydroxyurea, suggests that its transcriptional induction in response to hydroxyurea is regulated via CaNrm1, and biochemical analysis shows that hydroxyurea causes disruption of the interaction of CaNrm1 with CaSwi4. Furthermore, induction of the hyphal-specific genes is dampened under certain conditions in the Canrm1 -/- mutant, suggesting that the cell cycle transcription programme can influence the morphogenetic transcription programme of C.albicans. © 2012 Blackwell Publishing Ltd.


Kuznets G.,Technion IIT and the Rappaport Institute for Research in the Medical science | Vigonsky E.,Technion IIT and the Rappaport Institute for Research in the Medical science | Weissman Z.,Technion IIT and the Rappaport Institute for Research in the Medical science | Lalli D.,University of Florence | And 6 more authors.
PLoS Pathogens | Year: 2014

Iron scavenging constitutes a crucial challenge for survival of pathogenic microorganisms in the iron-poor host environment. Candida albicans, like many microbial pathogens, is able to utilize iron from hemoglobin, the largest iron pool in the host's body. Rbt5 is an extracellular glycosylphosphatidylinositol (GPI)-anchored heme-binding protein of the CFEM family that facilitates heme-iron uptake by an unknown mechanism. Here, we characterize an additional C. albicans CFEM protein gene, PGA7, deletion of which elicits a more severe heme-iron utilization phenotype than deletion of RBT5. The virulence of the pga7−/− mutant is reduced in a mouse model of systemic infection, consistent with a requirement for heme-iron utilization for C. albicans pathogenicity. The Pga7 and Rbt5 proteins exhibit distinct cell wall attachment, and discrete localization within the cell envelope, with Rbt5 being more exposed than Pga7. Both proteins are shown here to efficiently extract heme from hemoglobin. Surprisingly, while Pga7 has a higher affinity for heme in vitro, we find that heme transfer can occur bi-directionally between Pga7 and Rbt5, supporting a model in which they cooperate in a heme-acquisition relay. Together, our data delineate the roles of Pga7 and Rbt5 in a cell surface protein network that transfers heme from extracellular hemoglobin to the endocytic pathway, and provide a paradigm for how receptors embedded in the cell wall matrix can mediate nutrient uptake across the fungal cell envelope. © 2014 Kuznets et al.

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