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 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.

中文翻译：

---

PTPN23 结合动力蛋白接头 BICD1，是神经营养素受体内吞分选所必需的。

靶标衍生的神经营养素发出的信号对于神经系统的正确发育及其一生的维护至关重要。多年来，有关神经营养蛋白及其受体生命周期的几个方面已经得到表征，包括信号传导配体-受体复合物的形成、内吞作用和运输。然而，指导激活的神经营养素受体分类的分子机制仍然难以捉摸。此前，我们的实验室确定了动力蛋白运动适配器 Bicaudal-D1 (BICD1) 是脑源性神经营养因子 (BDNF) 激活的 TrkB（也称为 NTRK2）和 p75NTR（也称为 NGFR）溶酶体降解的关键因素。在运动神经元中。在这里，我们使用蛋白质组学方法，在 BICD1 相互作用组中鉴定了蛋白酪氨酸磷酸酶，非受体 23 型 (PTPN23)，它是运输 (ESCRT) 机器所需的内体分选复合体的成员。分子图谱显示 PTPN23 不是典型的 BICD1 货物；相反，PTPN23 结合 BICD1 的 N 末端，这对于细胞质动力蛋白的募集也至关重要。与 BICD1 敲低表型一致，PTPN23 的缺失导致 BDNF 激活的 p75NTR 和 TrkB 在肿胀的液泡样区室中积累增加，表明神经元 PTPN23 是神经营养蛋白受体内吞分选的新型调节剂。