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 FREs to enable extracellular heme uptake.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Varadi, M., Anyango, S., Deshpande, M., Nair, S., Natassia, C., Yordanova, G., Yuan, D., Stroe, O., Wood, G., Laydon, A., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkab1061 · Cited by 7,850 · see citing works
Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision
Bongomin, F., Gago, S., Oladele, R., & Denning, D. (2017) · Journal of Fungi · doi:10.3390/jof3040057 · Cited by 2,953 · see citing works
Nutritional immunity: transition metals at the pathogen–host interface
Hood, M. I., & Skaar, E. P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2836 · Cited by 1,535 · see citing works
Iron in infection and immunity
Cassat, J. E., & Skaar, E. P. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.04.010 · Cited by 1,214 · see citing works
Characterization of the oral fungal microbiome (mycobiome) in healthy individuals
Ghannoum, M. A., Jurevic, R. J., Mukherjee, P. K., Cui, F., Sikaroodi, M., Naqvi, A., & Gillevet, P. M. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000713 · Cited by 1,150 · see citing works
Iron homeostasis in host defence and inflammation
Ganz, T., & Nemeth, E. (2015) · Nature Reviews Immunology · doi:10.1038/nri3863 · Cited by 843 · see citing works
Chen, C., Pande, K., French, S. D., Tuch, B. B., & Noble, S. M. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.07.005 · Cited by 314 · see citing works
Ganz, T. (2018) · International Journal of Hematology · doi:10.1007/s12185-017-2366-2 · Cited by 270 · see citing works
Weissman, Z., & Kornitzer, D. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04199.x · Cited by 231 · see citing works
Self-citation<i>Candida albicans</i> iron acquisition within the host
Almeida, R. S., Wilson, D., & Hube, B. (2009) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2009.00570.x · Cited by 199 · see citing works
Iron Acquisition from Transferrin by <i>Candida albicans</i> Depends on the Reductive Pathway
Knight, S. A. B., Vilaire, G., Lesuisse, E., & Dancis, A. (2005) · Infection and Immunity · doi:10.1128/iai.73.9.5482-5492.2005 · Cited by 145 · see citing works
Singh, R. P., Prasad, H. K., Sinha, I., Agarwal, N., & Natarajan, K. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.233569 · Cited by 113 · see citing works
Weissman, Z., Shemer, R., & Kornitzer, D. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.02976.x · Cited by 88 · see citing works
Self-citationSaikia, S., Oliveira, D., Hu, G., & Kronstad, J. (2014) · Infection and Immunity · doi:10.1128/iai.01357-13 · Cited by 88 · see citing works
A role for complement receptor-like molecules in iron acquisition by Candida albicans
Moors, M. A., Stull, T. L., Blank, K. J., Buckley, H. R., & Mosser, D. M. (1992) · The Journal of experimental medicine · doi:10.1084/jem.175.6.1643 · Cited by 80 · see citing works
Hammacott, J. E., Williams, P. H., & Cashmore, A. M. (2000) · Microbiology · doi:10.1099/00221287-146-4-869 · Cited by 69 · see citing works
Differential activation of Staphylococcus aureus heme detoxification machinery by heme analogues
Wakeman, C. A., Stauff, D. L., Zhang, Y., & Skaar, E. P. (2014) · Journal of Bacteriology · doi:10.1128/jb.01067-13 · Cited by 45 · see citing works
Weissman, Z., Pinsky, M., Donegan, R. K., Reddi, A. R., & Kornitzer, D. (2020) · doi:10.1101/2020.07.26.221606 · Cited by 26 · see citing works
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Zheng, D., Zhang, X., Ding, J., Yue, D., Yang, F., & Li, Y. (2025) · Critical reviews in microbiology · doi:10.1080/1040841x.2025.2510256 · Cited by 10 · see citing works
- Authors
- Roy, U., Yaish, S., Weissman, Z., Pinsky, M., Dey, S., Horev, G., & Kornitzer, D.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Kornitzer, Daniel
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-10-06
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9635878
- OpenAlex
- W4302761464
- Cited by
- 32
- References
- 19
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 10 · 2022: 1
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Israel Science Foundation (587/19)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- heme acquisition, Candida albicans, plasma membrane, iron acquisition, substrate-binding domain, Saccharomyces cerevisiae
- MeSH terms
- Animals, Candida albicans, Fungal Proteins, Heme, Iron, FMN Reductase
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