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

Marta I Budzinska,Matthew Golding,Giampietro Schiavo,Anne Weston,Ambrosius P Snijders,David Villarroel-Campos,Lucy Collinson

doi:10.1242/jcs.242412

Abstract

ABSTRACTSignalling 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 ligand–receptor 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 p75NTR (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 p75NTR and TrkB in swollen vacuole-like compartments, suggesting that neuronal PTPN23 is a novel regulator of the endocytic sorting of neurotrophin receptors.

Highlights

Neurotrophins (NTs) control several aspects of neuronal development, including differentiation, dendritic branching, axonal growth and axon guidance (Oppenheim, 1989; Huang and Reichardt, 2001; Ascano et al, 2012; Garcia et al, 2009)
BICD1 interactors were ranked based on their presence in all BICD1 immunoprecipitates obtained from lysates of untreated and brain-derived neurotrophic factor (BDNF)-stimulated embryonic stem (ES)-MNs and N2AFLAG-TrkB cells, and characterised by gene ontology classifiers associated with intracellular transport and localisation as provided by the database for annotation, visualization and integrated discovery (DAVID, v6.8)
In non-neuronal cells, PTPN23 directly regulates the function of the endosomal sorting complexes required for transport (ESCRT) machinery, which controls the biogenesis of multivesicular bodies (MVBs) and their cargo degradation in lysosomes (Ali et al, 2013; Lee et al, 2016; Woodman, 2016; Gahloth et al, 2017)

Summary

Introduction

Neurotrophins (NTs) control several aspects of neuronal development, including differentiation, dendritic branching, axonal growth and axon guidance (Oppenheim, 1989; Huang and Reichardt, 2001; Ascano et al, 2012; Garcia et al, 2009). The NT family comprises nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3; known as NTF3) and NT-4/5 (NTF4 and NTF5), which activate two distinct classes of receptors: catalytic tropomyosin receptor kinase. Neurotrophins contribute to regulating neuronal plasticity, and play an integral part in establishing higher functions, such as learning, memory and behaviour (Cunha et al, 2010). They promote neuronal homeostasis, and their withdrawal is detrimental to the health of the nervous system (Mitre et al, 2017; Yamashita and Kuruvilla, 2016; Chen et al, 2017)

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