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

Carlos Martín-Rodríguez, Minseok Song, Begoña Anta, Francisco J González-Calvo, Rubén Deogracias, Deqiang Jing, Francis S Lee, Juan Carlos Arevalo

Journal of cell science 2020 Dec 23

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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. © 2020. Published by The Company of Biologists Ltd.

Citation

Carlos Martín-Rodríguez, Minseok Song, Begoña Anta, Francisco J González-Calvo, Rubén Deogracias, Deqiang Jing, Francis S Lee, Juan Carlos Arevalo. TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation. Journal of cell science. 2020 Dec 23;133(24)