A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis

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 + impor...

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Published inNature chemical biology Vol. 16; no. 3; pp. 337 - 344
Main Authors Garcia-Santamarina, Sarela, Probst, Corinna, Festa, Richard A., Ding, Chen, Smith, Aaron D., Conklin, Steven E., Brander, Søren, Kinch, Lisa N., Grishin, Nick V., Franz, Katherine J., Riggs-Gelasco, Pamela, Lo Leggio, Leila, Johansen, Katja Salomon, Thiele, Dennis J.
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.03.2020
Nature Publishing Group
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Summary: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 Cu 2+ 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. In the fungal pathogen Cryptococcus neoformans , Bim1 is a copper-binding lytic polysaccharide monooxygenase-like protein that participates in copper uptake in concert with the Ctr1 importer to drive virulence mechanisms during fungal meningitis.
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Chen Ding, College of Life and Health Sciences, Northeastern University, Shenyang, Liaoning, China
Steven E. Conklin, Division of Clinical Chemistry, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Richard A. Festa, Irvine Scientific, Santa Ana, California, USA
Sarela Garcia-Santamarina, Genome Biology Unit, Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
All authors of the manuscript, S.G.S, C.P., R.A.F., C.D., A.D.S, P.R.-G., S.E.C., S.B., L.N.K., L.L.L., K.J.F., N.V.G., K.S.J. and D.J.T. conducted and/or planned and interpreted experiments. C.P generated strains and conducted experiments in Fig 4 c-d, Fig S5 c, R. A. F conducted experiments in Fig 1 c-d, C. D. initiated the project, and generated strains and initial results, A. D. S. performed all mouse retro-orbital injections and participated in all mouse experiments, P.R.-G. planned, conducted and interpreted the results of all XAS experiments, S.E.C. and K.J.F conducted and/or planned and interpreted EPR experiments, S.B. and K.S.J. performed and/or planned and interpreted Bim1 activity experiments, L.N.K and N.V.G did bioinformatics analysis that led to the discovery of Bim1 as a LPMO-like protein, L.L.L. performed Bim1 homology modelling, S.G.S performed the rest of the experiments, S.G.S and D.J.T. planned and interpreted all experiments. All authors contributed to the writing and editing of the manuscript.
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ISSN:1552-4450
1552-4469
DOI:10.1038/s41589-019-0437-9