Phagocytosis and autophagy play critical roles in immune defense. The human fungal pathogen Cryptococcus neoformans (Cn) subverts host autophagy-initiation complex (AIC)-related proteins, to promote its phagocytosis and intracellular parasitism of host cells. The mechanisms by which the pathogen engages host AIC-related proteins remain obscure. Here, we show that the recruitment of host AIC proteins to forming phagosomes is dependent upon the activity of CD44, a host cell surface receptor that engages fungal hyaluronic acid (HA). This interaction elevates intracellular Ca2+ concentrations and activates CaMKKβ and its downstream target AMPKα, which results in activation of ULK1 and the recruitment of AIC components. Moreover, we demonstrate that HA-coated beads efficiently recruit AIC components to phagosomes and CD44 interacts with AIC components. Taken together, these findings show that fungal HA plays a critical role in directing the internalization and productive intracellular membrane trafficking of a fungal pathogen of global importance.

中文翻译：

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真菌透明质酸与宿主 CD44 之间的相互作用通过募集宿主自噬蛋白形成吞噬体来促进内化


吞噬作用和自噬在免疫防御中起关键作用。人真菌病原体新型隐球菌 （Cn） 破坏宿主自噬起始复合物 （AIC） 相关蛋白，促进其吞噬作用和宿主细胞的细胞内寄生作用。病原体与宿主 AIC 相关蛋白结合的机制仍然不清楚。在这里，我们表明宿主 AIC 蛋白的募集形成吞噬体取决于 CD44 的活性，CD44 是一种参与真菌透明质酸 （HA） 的宿主细胞表面受体。这种相互作用提高了细胞内 Ca2+ 浓度并激活了 CaMKKβ 及其下游靶标 AMPKα，从而导致 ULK1 激活和 AIC 组分的募集。此外，我们证明 HA 包被的珠子有效地将 AIC 成分募集到吞噬体中，并且 CD44 与 AIC 成分相互作用。综上所述，这些发现表明，真菌 HA 在指导具有全球重要性的真菌病原体的内化和生产性细胞内膜运输中起关键作用。