Fob1 and Fob2 proteins are virulence determinants of Rhizopus oryzae via facilitating iron uptake from Ferrioxamine
Open accessAbstract
Dialysis patients with chronic renal failure receiving deferoxamine for treating iron overload are uniquely predisposed for mucormycosis, which is most often caused by Rhizopus oryzae. Although the deferoxamine siderophore is not secreted by Mucorales, previous studies established that Rhizopus species utilize iron from ferrioxamine (iron-rich form of deferoxamine). Here we determined that the CBS domain proteins of Fob1 and Fob2 act as receptors on the cell surface of R. oryzae during iron uptake from ferrioxamine. Fob1 and Fob2 cell surface expression was induced in the presence of ferrioxamine and bound radiolabeled ferrioxamine. A R. oryzae strain with targeted reduced Fob1/Fob2 expression was impaired for iron uptake, germinating, and growing on medium with ferrioxamine as the sole source of iron. This strain also exhibited reduced virulence in a deferoxamine-treated, but not the diabetic ketoacidotic (DKA), mouse model of mucormycosis. The mechanism by which R. oryzae obtains iron from ferrioxamine involves the reductase/permease uptake system since the growth on ferrioxamine supplemented medium is associated with elevated reductase activity and the use of the ferrous chelator bathophenanthroline disulfonate abrogates iron uptake and growth on medium supplemented with ferrioxamine as a sole source of iron. Finally, R. oryzae mutants with reduced copies of the high affinity iron permease (FTR1) or with decreased FTR1 expression had an impaired iron uptake from ferrioxamine in vitro and reduced virulence in the deferoxamine-treated mouse model of mucormycosis. These two receptors appear to be conserved in Mucorales, and can be the subject of future novel therapy to maintain the use of deferoxamine for treating iron-overload.
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DFO can be used as an iron source because iron-laden DFO is ingested by Rhizopus oryzae through siderophore receptors Fob1 and Fob2.
“Although DFX is a semisynthetic compound, another iron chelator, DFO, can be used as an iron source as iron-laden DFO is ingested by Rhizopus oryzae through siderophore receptors Fob1 and Fob2 (Liu et al., 2015).”
From Iron in infection and immunity (2020) · cites this paper as Liu et al., 2015
The Discussion identifies iron-laden DFO (ferrioxamine) as an iron source for R. oryzae and Fob1/Fob2 as its cell-surface receptors. But its proposed primary mechanism is uptake of iron after ferrioxamine binds those receptors, not ingestion of the iron-laden DFO complex; it describes transport of the whole complex only as a possible secondary pathway. (LLM, conf=0.88)
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Iron in infection and immunity
Nairz, M., & Weiss, G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100864 · Cited by 359 · see citing works
- Authors
- Liu, M., Lin, L., Gebremariam, T., Luo, G., Skory, C. D., French, S. W., Chou, T.-F., Edwards, J. E., & Ibrahim, A. S.
- Affiliations
- University of California, Los Angeles (US)
- United States Department of Agriculture (US)
- Corresponding author
- Liu, Mingfu
- Lin, Lin
- Gebremariam, Teclegiorgis
- Luo, Guanpingsheng
- Skory, Christopher D.
- French, Samuel W.
- Chou, Tsui-Fen
- Edwards, John E.
- Ibrahim, Ashraf S.
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-05-14
- Volume
- 11
- Issue
- 5
- Pages
- e1004842
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC4431732
- OpenAlex
- W1537624486
- Cited by
- 62
- References
- 71
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 5 · 2018: 8 · 2017: 6
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS Pathogens (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, public-domain)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, public-domain)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI063503)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Rhizopus oryzae, Fob1, ferrioxamine, iron absorption, siderophore receptors, mucormycosis, deferoxamine, iron overload, reductase activity, fungal virulence, Mucorales
- MeSH terms
- Animals, Biological Transport, Deferoxamine, DNA-Binding Proteins, Ferric Compounds, Iron, Iron Chelating Agents, Membrane Glycoproteins, Mucormycosis, Rhizopus, Siderophores, Membrane Transport Proteins, Saccharomyces cerevisiae Proteins, Virulence Factors, Mice
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