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A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2020-01-13 , DOI: 10.1038/s41589-019-0437-9
Sarela Garcia-Santamarina 1, 2 , Corinna Probst 1 , Richard A Festa 1, 3 , Chen Ding 1, 4 , Aaron D Smith 1 , Steven E Conklin 5, 6 , Søren Brander 7 , Lisa N Kinch 8 , Nick V Grishin 8, 9 , Katherine J Franz 5 , Pamela Riggs-Gelasco 10 , Leila Lo Leggio 11 , Katja Salomon Johansen 7 , Dennis J Thiele 1, 12, 13
Affiliation  

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.



中文翻译:


一种裂解性多糖单加氧酶样蛋白在真菌铜输入和脑膜炎中发挥作用



真菌病原体新型隐球菌感染会导致致命性脑膜炎,主要发生在免疫功能低下的个体中。新型隐球菌在大脑中的定殖依赖于从宿主获取铜 (Cu),这驱动了关键的毒力机制。虽然新型隐球菌Cu +输入和毒力依赖于 Ctr1 和 Ctr4 蛋白,但对于参与这一过程的细胞外 Cu 配体知之甚少。我们鉴定了新型隐球菌基因BIM1 ,该基因在 Cu 限制期间被强烈诱导,并编码与裂解多糖单加氧酶 (LPMO) 相关的蛋白质。令人惊讶的是, bim1突变体缺乏 Cu,并且 Bim1 在 Cu 积累中的功能取决于 Cu 2+配位和通过糖磷脂酰肌醇锚定的细胞表面关联。 Bim1 与 Ctr1 协同参与铜的吸收,并且该通路的表达驱动小鼠感染模型中的大脑定植。这些研究证明了 LPMO 样蛋白作为真菌性脑膜炎中铜获取的关键因素。

更新日期:2020-01-13
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