Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 3, Pages 337-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-019-0437-9
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Funding
- United States National Institutes of Health (NIH) [GM041840, GM084176, GM127390]
- Welch Foundation [I-1505]
- German Research Foundation [PR 1727/1-1]
- NIH [GM100678-02, GM084146-S1]
- NIH Molecular Mycology and Pathogenesis Training program [5T32a1052080]
- Novo Nordisk Foundation [NNF17SA0027704]
- Duke University BioCoRE [R25-GM103765]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIH, National Institute of General Medical Sciences [P41GM103393]
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Infection by the fungal pathogen Cryptococcus neoformans causes lethal meningitis, primarily in immune-compromised individuals. Colonization of the brain by C. neoformans is dependent on copper (Cu) acquisition from the host, which drives critical virulence mechanisms. While C. neoformans Cu+ import and virulence are dependent on the Ctr1 and Ctr4 proteins, little is known concerning extracellular Cu ligands that participate in this process. We identified a C. neoformans gene, BIM1, that is strongly induced during Cu limitation and which encodes a protein related to lytic polysaccharide monooxygenases (LPMOs). Surprisingly, bim1 mutants are Cu deficient, and Bim1 function in Cu accumulation depends on Cu2+ coordination and cell-surface association via a glycophosphatidyl inositol anchor. Bim1 participates in Cu uptake in concert with Ctr1 and expression of this pathway drives brain colonization in mouse infection models. These studies demonstrate a role for LPMO-like proteins as a critical factor for Cu acquisition in fungal meningitis.
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