Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London, UK
Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London, UK.
EMBO J. 2014 Jul 17;33(14):1582-98. doi: 10.15252/embj.201387579. Epub 2014 Jun 11.
We have identified a new function for the dynein adaptor Bicaudal D homolog 1 (BICD1) by screening a siRNA library for genes affecting the dynamics of neurotrophin receptor-containing endosomes in motor neurons (MNs). Depleting BICD1 increased the intracellular accumulation of brain-derived neurotrophic factor (BDNF)-activated TrkB and p75 neurotrophin receptor (p75(NTR)) by disrupting the endosomal sorting, reducing lysosomal degradation and increasing the co-localisation of these neurotrophin receptors with retromer-associated sorting nexin 1. The resulting re-routing of active receptors increased their recycling to the plasma membrane and altered the repertoire of signalling-competent TrkB isoforms and p75(NTR) available for ligand binding on the neuronal surface. This resulted in attenuated, but more sustained, AKT activation in response to BDNF stimulation. These data, together with our observation that Bicd1 expression is restricted to the developing nervous system when neurotrophin receptor expression peaks, indicate that BICD1 regulates neurotrophin signalling by modulating the endosomal sorting of internalised ligand-activated receptors.
我们通过筛选影响运动神经元（MNs）中神经营养因子受体含有内体动力学的基因的 siRNA 文库，鉴定了动力蛋白适配器双尾域同源物 1（BICD1）的新功能。耗尽 BICD1 通过破坏内体分拣，减少溶酶体降解并增加这些神经营养因子受体与逆行相关分选连接蛋白 1 的共定位，增加了脑源性神经营养因子（BDNF）激活的 TrkB 和 p75 神经营养因子受体（p75（NTR））的细胞内积累。由此产生的活性受体再循环增加了它们向质膜的循环，并改变了神经元表面可用于配体结合的信号传导功能 TrkB 同工型和 p75（NTR）的谱。这导致 AKT 激活减弱，但更持久，以响应 BDNF 刺激。这些数据，以及我们观察到 Bicd1 表达在神经营养因子受体表达高峰期仅限于发育中的神经系统，表明 BICD1 通过调节内化配体激活受体的内体分拣来调节神经营养因子信号。
