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

Abstract

2Phagocytosis and autophagy play critical roles in immune defense. Cryptococcus neoformans (Cn), 3 a fungal pathogen that causes fatal infection, subverts the host autophagy initiation complex (AIC) 4 and its upstream regulatory proteins, to promote its phagocytosis and intracellular parasitism of 5 host cells. The mechanisms by which the pathogen engages host AIC proteins remain obscure. 6Here, we show that the recruitment of host AIC proteins to forming phagosomes is dependent 7 upon the activity of CD44, a host cell surface receptor that engages fungal hyaluronic acid (HA). 8This interaction elevates intracellular Ca 2+ concentrations and activates CaMKKb and its 9 downstream target AMPKα, which results in activation of ULK1 and the recruitment of AIC 10 components. Moreover, we demonstrate that HA-coated beads efficiently recruit AIC components 11 to phagosomes. Taken together, these findings show that fungal HA plays a critical role in 12 directing the internalization and productive intracellular membrane trafficking of a fungal 13 pathogen of global importance. 14 15 16 Ganley, I.G., Lam, D.H., Wang, J., Ding, X., Chen, S., and Jiang, X. (2009). ULK1· ATG13· FIP200 complex 1 mediates mTOR signaling and is essential for autophagy.