Abstract
The regulation of Trk receptors is critical for orchestrating multiple signalling pathways required for developing and maintaining neuronal networks. Activation of Trk receptors results in signalling, internalisation and subsequent degradation of the protein. Although ubiquitination of TrkA by Nedd4-2 has been identified as an important degradation pathway, much less is known about the pathways regulating the degradation of TrkB and TrkC. Critical to the interaction between TrkA and Nedd4-2 is a PPxY motif present within TrkA but absent in TrkB and TrkC. Given the absence of this interaction motif, it remains to be determined how TrkB and TrkC are ubiquitinated. Here we report that the adaptor protein Ndfip1 can interact with all three Trk receptors and show for TrkB the recruitment of Nedd4-2 through PPxY motifs present in Ndfip1. Ndfip1 mediates the ubiquitination of TrkB, resulting in receptor trafficking predominantly on Rab7 containing late endosomes, highlighting a pathway for TrkB degradation at the lysosome. In vitro, overexpression of Ndfip1 increased TrkB ubiquitination and decreased viability of BDNF-dependent primary neurons. In vivo, conditional genetic deletion of Ndfip1 increased TrkB in the brain and resulted in enlargement of the granular cell layer of the dentate gyrus.
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Acknowledgements
The TrkB construct was kindly provided by Dr. Junhua Xiao from the University of Melbourne.
Funding
This work was supported by the Australia National Health and Medical Research Council through Project Grants (grant numbers 1066925 and 1066895), and the Victorian Government through the Operational Infrastructure Scheme.
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All procedures were approved by the Florey Neuroscience Institutes Animal Ethics Committee.
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Murray, S.S., Wong, A.W., Yang, J. et al. Ubiquitin Regulation of Trk Receptor Trafficking and Degradation. Mol Neurobiol 56, 1628–1636 (2019). https://doi.org/10.1007/s12035-018-1179-5
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DOI: https://doi.org/10.1007/s12035-018-1179-5