Open AccessTrkB deubiquitination by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation
Author(s) -
Carlos Martín-Rodriguez,
Minseok Song,
B. Anta,
Francisco J González-Calvo,
Rubén Deogracias,
Dapeng Jing,
Francis S. Lee,
Juan Carlos Arévalo
Publication year - 2020
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.247841
Subject(s) - tropomyosin receptor kinase b , biology , low affinity nerve growth factor receptor , microbiology and biotechnology , ubiquitin , neurotrophin , brain derived neurotrophic factor , tropomyosin receptor kinase a , neurotrophic factors , receptor , biochemistry , gene
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.