TY - JOUR
T1 - A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis
AU - Garcia-Santamarina, Sarela
AU - Probst, Corinna
AU - Festa, Richard A.
AU - Ding, Chen
AU - Smith, Aaron D.
AU - Conklin, Steven E.
AU - Brander, Søren
AU - Kinch, Lisa N.
AU - Grishin, Nick V.
AU - Franz, Katherine J.
AU - Riggs-Gelasco, Pamela
AU - Lo Leggio, Leila
AU - Johansen, Katja Salomon
AU - Thiele, Dennis J.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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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U2 - 10.1038/s41589-019-0437-9
DO - 10.1038/s41589-019-0437-9
M3 - Article
C2 - 31932719
AN - SCOPUS:85078048138
SN - 1552-4450
VL - 16
SP - 337
EP - 344
JO - Nature chemical biology
JF - Nature chemical biology
IS - 3
ER -