PMID- 28500221 OWN - NLM STAT- MEDLINE DCOM- 20170814 LR - 20200225 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 37 IP - 25 DP - 2017 Jun 21 TI - Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB. PG - 5978-5995 LID - 10.1523/JNEUROSCI.3148-16.2017 [doi] AB - 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 suggest that the ubiquitination of TrkB is a mechanism that controls its downstream signaling pathways via the regulation of its endocytosis and postendocytic trafficking and that UCH-L1 mediates the deubiquitination of TrkB and could be a potential target for the modulation of hippocampus-dependent memory.SIGNIFICANCE STATEMENT Ubiquitin C-terminal hydrolase L1 (UCH-L1) has been demonstrated to play important roles in the regulation of synaptic plasticity and learning and memory. TrkB, the receptor for brain-derived neurotrophic factor, has also been shown to be a potent regulator of synaptic plasticity. In this study, we demonstrate that UCH-L1 functions as a deubiquitinase for TrkB. The blockage of UCH-L1-regulated deubiquitination of TrkB eventually results in the increased degradation of surface TrkB and decreased activation of TrkB and its downstream signaling pathways. In vivo, UCH-L1-regulated TrkB deubiquitination is necessary for hippocampus-dependent memory. Overall, our study provides novel insights into the mechanisms of UCH-L1-mediated neurobiological functions and suggests that ubiquitination is an important regulatory signal for TrkB functions. CI - Copyright (c) 2017 the authors 0270-6474/17/375978-18$15.00/0. FAU - Guo, Yun-Yun AU - Guo YY AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Lu, Yi AU - Lu Y AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Zheng, Yuan AU - Zheng Y AD - Department of Pediatrics, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, 250012, P.R. China. FAU - Chen, Xiao-Rong AU - Chen XR AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Dong, Jun-Lu AU - Dong JL AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Yuan, Rong-Rong AU - Yuan RR AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Huang, Shu-Hong AU - Huang SH AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Yu, Hui AU - Yu H AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Wang, Yue AU - Wang Y AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Chen, Zhe-Yu AU - Chen ZY AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and. FAU - Su, Bo AU - Su B AUID- ORCID: 0000-0003-4148-1202 AD - Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, and bxs103@sdu.edu.cn. LA - eng PT - Journal Article DEP - 20170512 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (ANA 12 compound) RN - 0 (Azepines) RN - 0 (Benzamides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 3.4.19.12 (Ubiquitin Thiolesterase) SB - IM MH - Animals MH - Azepines/pharmacology MH - Benzamides/pharmacology MH - Brain-Derived Neurotrophic Factor/metabolism/pharmacology MH - Conditioning, Operant/physiology MH - Endocytosis/genetics/physiology MH - Fear/psychology MH - Hippocampus/*physiology MH - Male MH - Memory/*physiology MH - Mice MH - Mice, Inbred C57BL MH - Motor Activity/drug effects/genetics/physiology MH - Neurons/metabolism MH - Receptor, trkB/antagonists & inhibitors/*metabolism MH - Signal Transduction/genetics/physiology MH - Ubiquitin Thiolesterase/genetics/*metabolism MH - Ubiquitination/genetics/*physiology PMC - PMC6596500 OTO - NOTNLM OT - TrkB OT - UCHL1 OT - endocytosis OT - learning and memory OT - recycling OT - ubiquitination EDAT- 2017/05/14 06:00 MHDA- 2017/08/15 06:00 PMCR- 2017/12/21 CRDT- 2017/05/14 06:00 PHST- 2016/10/08 00:00 [received] PHST- 2017/04/21 00:00 [revised] PHST- 2017/05/04 00:00 [accepted] PHST- 2017/05/14 06:00 [pubmed] PHST- 2017/08/15 06:00 [medline] PHST- 2017/05/14 06:00 [entrez] PHST- 2017/12/21 00:00 [pmc-release] AID - JNEUROSCI.3148-16.2017 [pii] AID - 3148-16 [pii] AID - 10.1523/JNEUROSCI.3148-16.2017 [doi] PST - ppublish SO - J Neurosci. 2017 Jun 21;37(25):5978-5995. doi: 10.1523/JNEUROSCI.3148-16.2017. Epub 2017 May 12.