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  1. Evaluation Summary:

    Iron acquisition is an essential problem for microbial growth and survival. Host defense mechanisms generally reduce iron availability and microbes often find themselves in iron poor environments. This study provides new insights into how the fungal pathogen Candida albicans obtains iron during infection.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    Here the authors aim to unravel the missing link between heme receptors and heme uptake into the cell and heme utilization. Previously, these authors uncovered the hemophore CSA2 and heme receptor RBT5 as the first steps in heme acquisition, but how heme is actually taken up by the cell and utilized as an Fe source was unknown. These authors identified the ferric reductase-like proteins Frp1 and Frp2 as having major roles in heme acquisition and utilization of heme as a sole Fe source. These are the first studies to demonstrate a role for members of the ferric reductase-like family in heme uptake and utilization. Although the exact mechanisms by which Frp1 and Frp2 affect the heme pathway are still unknown, these studies will inspire many new directions into microbial heme utilization at the host-pathogen interface. The paper is well written for a diverse audience, the experiments are comprehensive and the results are consistent with the conclusions.

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  3. Reviewer #2 (Public Review):

    The authors selected FRP1 and FRP2 for study based on homology to reductases and their genomic positions adjacent to the CFEM hemophores in the Candida genomes. Deletion strains showed heme-dependent growth defects both in plate assays and in liquid culture. Heterologous expression of genetically encoded cytoplasmic heme sensors confirmed that the strains lacking the FRPs exhibited defects in intracellular heme accumulation. Toxic metalloporphyrins, such as Ga-PPIX or Zn-PPIX, cause growth inhibition of strains competent for heme uptake, but the strains deleted for FRPs were resistant to the toxic effects. GFP-fusion proteins with FRPs were expressed in the ER but exhibited relocalization to the plasma membrane upon exposure to extracellular heme. CFEM proteins such as PGA7 exhibit homology to the N-terminal, heme-binding domains of other yeast ferric reductases. Co-expression of PGA7 and FRP1 restored growth in baker's yeast lacking heme biosynthesis, indicating a genetic interaction between the two. The manuscript does not explore potential physical interactions between PGA7 and FRPs, although a direct transfer of heme from one protein to the other is a logical hypothesis emanating from these studies.

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