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

Article and author information

Author details

  1. Udita Roy

    Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Shir Yaish

    Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Ziva Weissman

    Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Mariel Pinsky

    Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Sunanda Dey

    Department of Molecular Microbiology, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Guy Horev

    Bioinformatics Knowledge Unit, Technion - Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. 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.
    ORCID icon "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.

Reviewing Editor

  1. Arturo Casadevall, Johns Hopkins Bloomberg School of Public Health, United States

Version history

  1. Preprint posted: May 25, 2022 (view preprint)
  2. Received: May 26, 2022
  3. Accepted: October 5, 2022
  4. Accepted Manuscript published: October 6, 2022 (version 1)
  5. Version of Record published: November 4, 2022 (version 2)

Copyright

© 2022, Roy et al.

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.

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  1. Udita Roy
  2. Shir Yaish
  3. Ziva Weissman
  4. Mariel Pinsky
  5. Sunanda Dey
  6. Guy Horev
  7. Daniel Kornitzer
(2022)
Ferric reductase-related proteins mediate fungal heme acquisition
eLife 11:e80604.
https://doi.org/10.7554/eLife.80604

Share this article

https://doi.org/10.7554/eLife.80604

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