Ding Shengli, Yang Jing, Feng Xuehuan, Pandey Aseem, Barhoumi Rola, Zhang Dongmei, Bell Samantha L, Liu Yue, da Costa Luciana Fachini, Rice-Ficht Allison, Watson Robert O, Patrick Kristin L, Qin Qing-Ming, Ficht Thomas A, de Figueiredo Paul
College of Plant Sciences & Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, Jilin 130062, China.
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX 77807, USA.
iScience. 2021 Feb 12;24(3):102192. doi: 10.1016/j.isci.2021.102192. eCollection 2021 Mar 19.
Phagocytosis and autophagy play critical roles in immune defense. The human fungal pathogen (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 Ca 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.
吞噬作用和自噬在免疫防御中发挥着关键作用。人类真菌病原体新型隐球菌（Cn）会破坏宿主自噬起始复合物（AIC）相关蛋白，以促进其对宿主细胞的吞噬作用和细胞内寄生。病原体与宿主AIC相关蛋白结合的机制仍不清楚。在这里，我们表明宿主AIC蛋白募集到正在形成的吞噬体上依赖于CD44的活性，CD44是一种与真菌透明质酸（HA）结合的宿主细胞表面受体。这种相互作用会提高细胞内钙离子浓度并激活CaMKKβ及其下游靶点AMPKα，从而导致ULK1的激活和AIC组分的募集。此外，我们证明HA包被的珠子能有效地将AIC组分募集到吞噬体上，并且CD44与AIC组分相互作用。综上所述，这些发现表明真菌HA在指导一种具有全球重要性的真菌病原体的内化和有效的细胞内膜运输中起着关键作用。
