Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Yun-Yun GuoBo Su

Abstract

Multiple studies have established that brain-derived neurotrophic factor (BDNF) plays a critical role in the regulation of synaptic plasticity via its receptor, TrkB. In addition to being phosphorylated, TrkB has also been demonstrated to be ubiquitinated. However, the mechanisms of TrkB ubiquitination and its biological functions remain poorly understood. In this study, we demonstrate that ubiquitin C-terminal hydrolase L1 (UCH-L1) promotes contextual fear conditioning learning and memory via the regulation of ubiquitination of TrkB. We provide evidence that UCH-L1 can deubiquitinate TrkB directly. K460 in the juxtamembane domain of TrkB is the primary ubiquitination site and is regulated by UCH-L1. By using a peptide that competitively inhibits the association between UCH-L1 and TrkB, we show that the blockade of UCH-L1-regulated TrkB deubiquitination leads to increased BDNF-induced TrkB internalization and consequently directs the internalized TrkB to the degradation pathway, resulting in increased degradation of surface TrkB and attenuation of TrkB activation and its downstream signaling pathways. Moreover, injection of the peptide into the DG region of mice impairs hippocampus-dependent memory. Together, our results sugges...Continue Reading

Citations

Sep 20, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yunyun GuoChengjiang Gao
Jul 6, 2019·EMBO Molecular Medicine·Gonzalo S TejedaMargarita Díaz-Guerra
Dec 9, 2020·Journal of Cell Science·Carlos Martín-RodríguezJuan Carlos Arevalo
Jan 24, 2021·Cell Death & Disease·Fatima Amer-SarsourAvraham Ashkenazi
Aug 4, 2020·Neurobiology of Learning and Memory·Madeline MusausTimothy J Jarome
Apr 2, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Xiaorong ChenChengjiang Gao

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