A Phosphatidylinositol 4,5-bisphosphate Redistribution-based Sensing Mechanism Initiates A Phagocytosis Programing

Receptor-based phagocytosis is an evolutionarily recent event.However,the primordial solid structure uptake is a defining feature of eukaryotic biology that had existed prior to phagocytic receptors.In our lab we proposed several years ago that solid particle binding to a phagocyte surface triggers membrane lipid domain sorting.This redistribution leads to a strong phagocytic programing and its signaling cascade recapitulates the entire molecular events of FcR-based phagocytosis with complete dependence on Src family kinases,Syk,and phosphoinositide 3-kinase(PI3K).But the mechanism from lipid sorting to Syk signaling activation is still unclear.In this research we used a generic Immunoreceptor Tyrosine-based Activation Motif(ITAM)sequence as a probe and identified membrane proximal phagocytic signaling transducers from the mouse genome.We report here that a solid structure binding to the cell surface leads to autonomous accumulation of phosphatidylinositol 4,5-bisphosphate(PIP2)to the site of contact,which attracts a conserved structural linker,Moesin,to the plasma membrane.An ITAM-like domain contained Moesin trans-activates a phagocytic programming including Syk and downstream signaling that is essentially identical to that initiated by Fc receptors.To identify the origin of PIP2-Moesin signaling,preliminary phylogenic analyses based on model organisms were performed.The analysis identified this Moesin-based signaling to a hypothetic conjecture predating modern Fc and immune receptors.This work therefore reveals a signaling platform for the evolutionarily conserved phagocytosis that provides essential components for modern ITAM-based signaling cascades.