摘要：SummaryPhagocytosis and autophagy play critical roles in immune defense. The human fungal pathogenCryptococcus 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.Graphical abstractDisplay OmittedHighlights•Fungal HA drives non-canonical and ligand-induced autophagy in phagocytic cells•Cn recruits host CD44 to forming phagocytic cups to initiate fungal internalization•Fungal HA-CD44 interactions elevate intracellular Ca2+levels and activate CaMKKβ•A Ca2+-CaMKKβ-AMPK-ULK1 signaling axis is involved in HA-CD44 induced autophagyImmunology; Mycology
