TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • December 23, 2020

Research

keywords

  • Brain-Derived Neurotrophic Factor
  • Receptor, trkB

Identity

PubMed Central ID

  • PMC7774901

Scopus Document Identifier

  • 85099916871

Digital Object Identifier (DOI)

  • 10.1074/jbc.M112.425272

PubMed ID

  • 33288548

Additional Document Info

volume

  • 133

issue

  • 24