KCTD13-mediated ubiquitination and degradation of GluN1 regulates excitatory synaptic transmission and seizure susceptibility

作者全名："Gu, Juan; Ke, Pingyang; Guo, Haokun; Liu, Jing; Liu, Yan; Tian, Xin; Huang, Zhuo; Xu, Xin; Xu, Demei; Ma, Yuanlin; Wang, Xuefeng; Xiao, Fei"

作者地址："[Gu, Juan; Ke, Pingyang; Guo, Haokun; Liu, Jing; Liu, Yan; Tian, Xin; Xu, Xin; Xu, Demei; Ma, Yuanlin; Wang, Xuefeng; Xiao, Fei] Chongqing Med Univ, Dept Neurol, Chongqing Key Lab Neurol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Gu, Juan] Southwest Med Univ, Dept Neurol, Affiliated Tradit Chinese Med Hosp, Luzhou 646000, Peoples R China; [Huang, Zhuo] Peking Univ, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, State Key Lab Nat & Biomimet Drugs,Hlth Sci Ctr, Beijing 100191, Peoples R China; [Xiao, Fei] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China"

通信作者："Wang, XF; Xiao, F (通讯作者)，Chongqing Med Univ, Dept Neurol, Chongqing Key Lab Neurol, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Xiao, F (通讯作者)，Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China."

来源：CELL DEATH AND DIFFERENTIATION

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000981375200002

JCR分区：Q1

影响因子：13.7

年份：2023

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文献类型：Article; Early Access

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摘要："Temporal lobe epilepsy (TLE) is the most common and severe form of epilepsy in adults; however, its underlying pathomechanisms remain elusive. Dysregulation of ubiquitination is increasingly recognized to contribute to the development and maintenance of epilepsy. Herein, we observed for the first time that potassium channel tetramerization domain containing 13 (KCTD13) protein, a substrate-specific adapter for cullin3-based E3 ubiquitin ligase, was markedly down-regulated in the brain tissue of patients with TLE. In a TLE mouse model, the protein expression of KCTD13 dynamically changed during epileptogenesis. Knockdown of KCTD13 in the mouse hippocampus significantly enhanced seizure susceptibility and severity, whereas overexpression of KCTD13 showed the opposite effect. Mechanistically, GluN1, an obligatory subunit of N-methyl-D-aspartic acid receptors (NMDARs), was identified as a potential substrate protein of KCTD13. Further investigation revealed that KCTD13 facilitates lysine-48-linked polyubiquitination of GluN1 and its degradation through the ubiquitin-proteasome pathway. Besides, the lysine residue 860 of GluN1 is the main ubiquitin site. Importantly, dysregulation of KCTD13 affected membrane expression of glutamate receptors and impaired glutamate synaptic transmission. Systemic administration of the NMDAR inhibitor memantine significantly rescued the epileptic phenotype aggravated by KCTD13 knockdown. In conclusion, our results demonstrated an unrecognized pathway of KCTD13-GluN1 in epilepsy, suggesting KCTD13 as a potential neuroprotective therapeutic target for epilepsy."

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