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

Nature chemical biology 2020 Mar

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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.

Citation

Sarela Garcia-Santamarina, Corinna Probst, Richard A Festa, Chen Ding, Aaron D Smith, Steven E Conklin, Søren Brander, Lisa N Kinch, Nick V Grishin, Katherine J Franz, Pamela Riggs-Gelasco, Leila Lo Leggio, Katja Salomon Johansen, Dennis J Thiele. A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis. Nature chemical biology. 2020 Mar;16(3):337-344