Ferric reductase-related proteins mediate fungal heme acquisition

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Abstract

Heme can serve as iron source in many environments, including the iron-poor animal host environment. The fungal pathobiont Candida albicans expresses a family of extracellular CFEM hemophores that capture heme from host proteins and transfer it across the cell wall to the cell membrane, to be endocytosed and utilized as heme or iron source. Here we identified Frp1 and Frp2, two ferric reductase (FRE)-related proteins that lack an extracellular N-terminal substrate-binding domain, as being required for hemoglobin heme utilization and for sensitivity to toxic heme analogs. Frp1 and Frp2 redistribute to the plasma membrane in the presence of hemin, consistent with a direct role in heme trafficking. Expression of Frp1 with the CFEM hemophore Pga7 can promote heme utilization in Saccharomyces cerevisiae as well, confirming the functional interaction between these proteins. Sequence and structure comparison reveals that the CFEM hemophores are related to the FRE substrate-binding domain that is missing in Frp1/2. We conclude that Frp1/2 and the CFEM hemophores form a functional complex that evolved from ferric reductases to enable extracellular heme uptake.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. A sequence alignment summary file used for phylogenetic profiling analysis is available on Github at https://github.com/BKU-Technion/FRP

The following previously published data sets were used

1. Grigoriev IV
2. et al
(2015) MycoCosm portal: gearing up for 1000 fungal genomes
https://mycocosm.jgi.doe.gov/mycocosm/home.

https://mycocosm.jgi.doe.gov/mycocosm/home
(2015) "Candida Genome Database"
http://www.candidagenome.org/download/.

http://www.candidagenome.org

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Udita Roy

Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel

Competing interests
The authors declare that no competing interests exist.
Shir Yaish

Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel

Competing interests
The authors declare that no competing interests exist.
Ziva Weissman

Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel

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The authors declare that no competing interests exist.
Mariel Pinsky

Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel

Competing interests
The authors declare that no competing interests exist.
Sunanda Dey

Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel

Competing interests
The authors declare that no competing interests exist.
Guy Horev

Bioinformatics Knowledge Unit, Technion - Israel Institute of Technology, Haifa, Israel

Competing interests
The authors declare that no competing interests exist.
Daniel Kornitzer

Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel

For correspondence
danielk@technion.ac.il

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5062-2735

Funding

Israel Science Foundation (587/19)

Daniel Kornitzer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.