Ubiquitin Regulation of Trk Receptor Trafficking and Degradation

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.

TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation

“…Supporting this statement, it has been reported that the postendocytic fates of TrkA and TrkB are different (Chen et al, 2005). TrkA is mainly recycled back to plasma membrane once is activated to undergo many rounds of activation and recycling, whereas TrkB is mainly sent to the degradative pathway through the lysosome (Chen et al, 2005;Terenzio et al, 2014;Murray et al, 2019), but not proteasome (Fig S3). Therefore, it is possible that USP8 may exert opposite effects on different substrates that perform the same function.…”

“…Together, our results indicate that USP8 protein modulates dendrite formation in hippocampal neurons in response to BDNF. (Pandya et al, 2014), UCH-L1 as DUB for TrkB (Guo et al, 2017) and Ndfip1, a HECT E3 ubiquitin ligases adaptor, as a protein that regulates TrkB ubiquitination (Murray et al, 2019), have been reported. In addition, an amino acid consensus motif for TRAF6/p62 ubiquitination has been proposed for TrkB (Jadhav et al, 2011), although it remains to be addressed whether TRAF6/p62 directly ubiquitinates TrkB.…”

“…However, very little is known about TrkB and TrkC ubiquitination. It has been reported that c-Cbl E3 ubiquitin ligase can ubiquitinate TrkB (Pandya et al, 2014) and that Ndfip1, and adaptor protein of HECT E3 ubiquitin ligases, mediates ubiquitination of TrkB receptor and degradation (Murray et al, 2019). In addition, UCH-L1 deubiquitinates TrkB promoting TrkBdependent contextual fear conditioning learning and memory (Guo et al, 2017).…”

Nitric oxide-induced tyrosine nitration of TrkB impairs BDNF signaling and restrains neuronal plasticity

“…Both the nitrated and the phosphorylated TRKB C-terminal peptides were also found to interact more with the endogenous AP2M compared to the control peptide (Fig 3D). Finally, since TRKB ubiquitination has been shown to mediate its endocytosis and degradation upon phosphorylation (Murray et al, 2019), we tested if nitration would affect TRKB interaction with ubiquitin, and endocytosis. SNP increased TRKB ubiquitination (Fig 3E) and reduced TRKB positioning on the neuronal cell surface (Fig 3F).…”

microRNA‐454‐mediated NEDD4‐2/TrkA/cAMP axis in heart failure: Mechanisms and cardioprotective implications

“…The activation of NEDD4‐2 is correlated with oxidative stress in hypertension 12 . Existing literature has highlighted the ubiquitination of tropomyosin receptor kinase A (TrkA) by NEDD4‐2 as a crucial degradation pathway required in the maintenance of neuronal networks 13 . Depletion of NEDD4‐2 is also reported to activate TrkA signalling 14 .…”