Neuronal differentiation through GPI-anchor cleavage by GDE2: regulation via sequence-dependent trafficking

GDE2 is a six-transmembrane glycerophosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby influences biological signaling cascades. GDE2 promotes neuronal differentiation cell-autonomously through glypican cleavage and is a prognostic marker in neuroblastoma, while GDE2 deficiency causes progressive neurodegeneration in mice and developmental defects in zebrafish. However, the regulation of GDE2 remains unclear. Here we show that in undifferentiated neuronal cells, GDE2 undergoes constitutive internalization and traffics back along both fast and slow recycling routes, while a small percentage is sorted to late endosomes. GDE2 trafficking is dictated by distinctive C-terminal tail sequences that determine secretion, endocytosis and recycling preference, respectively, and thereby regulate GDE2 function both positively and negatively. Our study reveals the sequence determinants of GDE2 trafficking and surface localization, and provides insight into the control of GPI-anchored protein activities with potential implications for nervous system disorders associated with impaired trafficking and beyond.