Interactions between fungal hyaluronic acid and host CD44 promote internalization by recruiting host autophagy proteins to forming phagosomes

Summary Phagocytosis and autophagy play critical roles in immune defense. Cryptococcus neoformans (Cn), a fungal pathogen that causes fatal infection, subverts the host autophagy initiation complex (AIC) and its upstream regulatory proteins, to promote its phagocytosis and intracellular parasitism of host cells. The mechanisms by which the pathogen engages host AIC 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 2+ 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. 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. Graphical Abstract In Brief Ding et al. reveal that interactions between fungal hyaluronic acid (HA) and host CD44 activate a Ca 2+ - CaMKKβ-AMPK-ULK1 signaling pathway that recruits autophagy initiation complex components to forming phagosomes to drive fungal internalization. Highlights Fungal HA interactions with host cells drive a novel non-canonical, ligand-induced, autophagy pathway in phagocytic cells Cryptococcus neoformans recruits host CD44, together with AIC components and regulatory proteins, to forming phagocytic cups to initiate host cell internalization Fungal HA interactions with CD44 on host cell surfaces elevate intracellular Ca 2+ concentrations, leading to activation of CaMKKβ A Ca 2+ -CaMKKβ-AMPK-ULK1 signaling axis is involved in HA and CD44 induced autophagy protein recruitment during Cn internalization