Endophilin B1

Abstract

Endophilin B1 is a member of the endophilin family that is localized predominantly to intracellular membranes. Also known as Bax-interacting factor-1 (Bif-1), this protein has been observed to regulate the membrane dynamics of various intracellular compartments, such as the control of mitochondrial morphology and autophagosome formation in fibroblast. Endophilin B1 is expressed in the brain, but its functions in neurons had remained unknown. Recently, we have observed a novel role of endophilin B1 in neurons where it controls the trafficking of TrkA, cognate receptor for the prototypic neurotrophin nerve growth factor (NGF). Knock-down of endophilin B1 expression induces precocious targeting of NGF/TrkA to late endosomes and lysosomes, thereby leading to reduced TrkA levels. This is accompanied by marked attenuation of NGF-induced gene transcription and neurite outgrowth. Our observations suggest that endophilin B1 regulates TrkA level and downstream functions by controlling the movement of TrkA to late endosomes/lysosomes, possibly acting at the level of early endosomes.

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Acknowledgements

This work was supported in part by the Research Grants Council of Hong Kong (HKUST 6119/04M, 6431/06M, 661007 and HKUST 1/06C) and the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01). We thank Ka Chun Lok for his excellent help in preparing the figure.

Figures and Tables

Figure 1 A schematic depicting the potential role of endophilin B1 in NGF/TrkA trafficking and downstream function. Binding of NGF to TrkA triggers internalization of the NGF/TrkA complex through clathrin-mediated endocytosis. Subsequent to clathrin uncoating, the vesicles containing the internalized NGF/TrkA complex fuse with early endosomes, where endophilin B1 interacts and co-localizes extensively with early endosome marker EEA1. Endophilin B1 possibly controls the trafficking of internalized NGF/TrkA from early endosomes to late endosomes, as knock-down of endophilin B1 expression results in premature targeting of TrkA to late endosomes and lysosomes, leading to reduced total TrkA level. Endophilin B1 also appears to facilitate recycling of NGF/TrkA to the cell surface. Nonetheless, whether endophilin B1 regulates endocytosis and the trafficking of NGF/TrkA from plasma membrane to early endosomes remain to be elucidated. Our data suggest that by preventing precocious targeting of NGF/TrkA to the degradation pathway, endophilin B1 preserves TrkA level and contributes to Erk1/2 activation on endosomes, thereby enabling NGF-induced neurite outgrowth.

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