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TrkB deubiquitination by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation.

Ubiquitination of receptor tyrosine kinases (RTK) regulates both the levels and functions of these receptors. TrkB neurotrophin receptor, a RTK, is ubiquitinated upon activation by the brain-derived neurotrophic factor (BDNF) binding. Although TrkB ubiquitination has been demonstrated, there is a lack of knowledge regarding the precise repertoire of proteins that regulates TrkB ubiquitination. Here, we provide mechanistic evidence indicating that ubiquitin carboxyl-terminal hydrolase 8 (USP8) modulates BDNF/TrkB-dependent neuronal differentiation. USP8 binds to the C-terminus of TrkB using its microtubule interacting domain (MIT). Immunopurified USP8 deubiquitinates TrkB in vitro whereas knockdown of USP8 results in enhanced ubiquitination of TrkB upon BDNF treatment in neurons. As a consequence of USP8 depletion, TrkB levels and its activation were reduced. Moreover, USP8 protein regulates the differentiation and proper 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.