Exogenous lipid vesicles induce endocytosis-mediated cellular aggregation in a close unicellular relative of animals

Capsaspora owczarzaki is a protozoan that may both reveal aspects of animal evolution and also curtail the spread of schistosomiasis, a neglected tropical disease. Capsaspora exhibits a chemically regulated aggregative behavior that resembles cellular aggregation in some animals. This behavior may have played a key role in the evolution of animal multicellularity. Additionally, this aggregative behavior may be important for Capsaspora 's ability to colonize the intermediate host of parasitic schistosomes and potentially prevent the spread of schistosomiasis. Both applications demand elucidation of the molecular mechanism of Capsaspora aggregation. Toward this goal, we first determined the necessary chemical properties of lipid cues that activate aggregation. We found that a wide range of abundant zwitterionic lipids induced aggregation, revealing that the aggregative behavior could be activated by diverse lipid-rich conditions. Furthermore, we demonstrated that aggregation in Capsaspora requires clathrin-mediated endocytosis, highlighting the potential significance of endocytosis-linked cellular signaling in recent animal ancestors. Finally, we found that aggregation was initiated by post-translational activation of cell-cell adhesion-not transcriptional regulation of cellular adhesion machinery. Our findings illuminate the chemical, molecular and cellular mechanisms that regulate Capsaspora aggregative behavior-with implications for the evolution of animal multicellularity and the transmission of parasites.