Ubiquitylation of receptor tyrosine kinases (RTKs) regulates both the levels and functions of these receptors. The neurotrophin receptor TrkB (also known as NTRK2), a RTK, is ubiquitylated upon activation by brain-derived neurotrophic factor (BDNF) binding. Although TrkB ubiquitylation has been demonstrated, there is a lack of knowledge regarding the precise repertoire of proteins that regulates TrkB ubiquitylation. Here, we provide mechanistic evidence indicating that ubiquitin carboxyl-terminal hydrolase 8 (USP8) modulates BDNF- and TrkB-dependent neuronal differentiation. USP8 binds to the C-terminus of TrkB using its microtubule-interacting domain (MIT). Immunopurified USP8 deubiquitylates TrkB in vitro, whereas knockdown of USP8 results in enhanced ubiquitylation of TrkB upon BDNF treatment in neurons. As a consequence of USP8 depletion, TrkB levels and its activation are reduced. Moreover, USP8 protein regulates the differentiation and correct BDNF-dependent dendritic formation of hippocampal neurons in vitro and in vivo. We conclude that USP8 positively regulates the levels and activation of TrkB, modulating BDNF-dependent neuronal differentiation.

This article has an associated First Person interview with the first author of the paper.

受体酪氨酸激酶 (RTK) 的泛素化可调节这些受体的水平和功能。神经营养蛋白受体 TrkB（也称为 NTRK2）是一种 RTK，在脑源性神经营养因子 (BDNF) 结合激活后被泛素化。尽管 TrkB 泛素化已得到证实，但仍缺乏关于调节 TrkB 泛素化的精确蛋白质库的知识。在这里，我们提供了机制证据，表明泛素羧基末端水解酶 8 (USP8) 调节 BDNF 和 TrkB 依赖性神经元分化。USP8 使用其微管相互作用结构域 (MIT) 与 TrkB 的 C 末端结合。免疫纯化的 USP8在体外使 TrkB 去泛素化，而 USP8 的敲除会导致神经元中 BDNF 处理后 TrkB 的泛素化增强。由于 USP8 耗尽，TrkB 水平及其激活降低。此外，USP8蛋白在体外和体内调节海马神经元的分化和纠正BDNF依赖的树突形成。我们得出结论，USP8 正向调节 TrkB 的水平和激活，调节 BDNF 依赖性神经元分化。

本文有对该论文第一作者的相关第一人称采访。