title: A relay network of extracellular heme-binding proteins drives C. albicans iron acquisition from hemoglobin.
abstract: 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.
authors.affiliation: B. Rappaport Faculty of Medicine, Technion - I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Kuznets
authors.affiliation: B. Rappaport Faculty of Medicine, Technion - I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Vigonsky
authors.affiliation: B. Rappaport Faculty of Medicine, Technion - I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Ziva
authors.initials: Z
authors.lastname: Weissman
authors.affiliation: CERM and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Lalli
authors.affiliation: B. Rappaport Faculty of Medicine, Technion - I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Tsvia
authors.initials: T
authors.lastname: Gildor
authors.affiliation: Microbiology Department, University of Tennessee, Knoxville, Tennessee, United States of America.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Kauffman
authors.affiliation: CERM and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Turano
authors.affiliation: Microbiology Department, University of Tennessee, Knoxville, Tennessee, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Becker
authors.affiliation: B. Rappaport Faculty of Medicine, Technion - I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Lewinson
authors.affiliation: B. Rappaport Faculty of Medicine, Technion - I.I.T. and the Rappaport Institute for Research in the Medical Sciences, Haifa, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kornitzer
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000378:metabolism* / Q000472:pathogenicity; D002352:Carrier Proteins / Q000378:metabolism*; D002473:Cell Wall / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D000081062:Heme-Binding Proteins; D006420:Hemeproteins / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D014774:Virulence / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D017261:Glycosylphosphatidylinositols; D000081062:Heme-Binding Proteins; D006420:Hemeproteins; D006454:Hemoglobins; D006418:Heme; D007501:Iron