PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors

Abstract

Signalling by target-derived neurotrophins is essential for the correct development of the nervous system and its maintenance throughout life. Several aspects concerning the lifecycle of neurotrophins and their receptors have been characterised over the years, including the formation, endocytosis and trafficking of signalling-competent ligandreceptor complexes. However, the molecular mechanisms directing the sorting of activated neurotrophin receptors are still elusive. Previously, our laboratory identified Bicaudal-D1 (BICD1), a dynein motor adaptor, as a key factor for lysosomal degradation of brain-derived neurotrophic factor (BDNF)-activated TrkB (also known as NTRK2) and p75 NTR (also known as NGFR) in motor neurons. Here, using a proteomics approach, we identified protein tyrosine phosphatase, non-receptor type 23 (PTPN23), a member of the endosomal sorting complexes required for transport (ESCRT) machinery, in the BICD1 interactome. Molecular mapping revealed that PTPN23 is not a canonical BICD1 cargo; instead, PTPN23 binds the N-terminus of BICD1, which is also essential for the recruitment of cytoplasmic dynein. In line with the BICD1-knockdown phenotype, loss of PTPN23 leads to increased accumulation of BDNF-activated p75 NTR and TrkB in swollen vacuolelike compartments, suggesting that neuronal PTPN23 is a novel regulator of the endocytic sorting of neurotrophin receptors.

Retrograde transport defects inMunc18-1null neurons explain abnormal Golgi morphology

“…Hence, we conclude that the retrograde trafficking defects occur after the initial endocytosis of CTB/TrkB. Indeed, perturbations in retrograde transport of signalling endosomes in Endophilin triple KO neurons or inhibition of dynein motor proteins result in similar cellular phenotypes and reduced survival, albeit less pronounced, as presented in this study (Burk et al, 2017;Budzinska et al, 2020). Hence, defects in retrograde transport of signalling endosomes provide a plausible explanation for the observed abnormalities in CTB transport and retrograde TrkB trafficking, and also for the reduced Golgi size in Munc18-1 KO neurons.…”

“…The impairment in retrograde transport might not only provide an explanation for the Golgi abnormalities, but also for the fact that Munc18-1 KO neurons die. Correct retrograde transport of TrkB is essential for neuronal survival (Reichardt, 2006;Burk et al, 2017), and comparable abnormalities in TrkB-containing endosomes have been reported upon perturbations of the retrograde pathways, leading to defective neurotrophic signalling and reduced neuronal survival (Wan et al, 2008;Budzinska et al, 2020). In addition, enlarged signalling endosomes have directly been linked to neurodegenerative processes (Xu et al, 2016).…”

“…To further investigate the impaired retrograde trafficking, we examined the retrograde endosomal trafficking of TrkB using live labelling with a TrkB antibody (Carrodus et al, 2014;Barford et al, 2017;Budzinska et al, 2020). Before antibody incubation, the mean TrkB surface labelling was similar in WT and Munc18-1 KO neurons (Fig.…”

Loss of MUNC18‐1 leads to retrograde transport defects in neurons

“…To further investigate the impaired retrograde pathways, we examined the retrograde endosomal pathway of TrkB using live labelling with a TrkB antibody (Barford et al, 2017; Budzinska et al, 2020; Carrodus et al, 2014). First, TrkB surface expression was assessed in fixed neurons prior to permeabilization.…”

“…In contrast, correct retrograde signalling of TrkB is critical for neuronal survival (Burk et al, 2017;Reichardt, 2006). Comparable abnormalities in TrkBcontaining endosomes have been reported upon perturbations of the retrograde pathways, leading to defective neurotrophic signalling and reduced neuronal survival (Budzinska et al, 2020;Wan et al, 2008).…”