Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity
Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity
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DNMT3a 的 Ube2b 依赖性降解减轻了阿片诱导的突触和行为可塑性的转录制动
DOI：
10.1038/s41380-019-0533-y
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发表时间：
2021-04-01
影响因子：
11
通讯作者：
Liu, Jing-Gen
中科院分区：
文献类型：
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作者：
Chen, Zhong-Guo;Wang, Yu-Jun;Liu, Jing-Gen
令人信服的证据表明，由肌动蛋白细胞骨架重塑驱动的突触结构可塑性，是成瘾药物诱导的长期行为可塑性的基础。然而，导致肌动蛋白细胞骨架重塑的信号机制仍不清楚。DNA甲基化是控制活性依赖的基因表达的关键机制，对长时间的突触可塑性至关重要。在这里，我们提供了证据表明，DNA甲基转移酶DNMT3a被E2泛素结合酶Ube2b介导的背侧海马区泛素化(Ube2b)所降解。DNMT3A的降解导致CAMKK1基因启动子去甲基化，从而促进CAMKK1的表达，进而激活其下游靶标CaMK1α，CaMK1是脊椎发生的重要调节因子。CAMKK1/CaMKIα信号通路通过激活Rac鸟嘌呤核苷酸交换因子βPIX来调节肌动蛋白细胞骨架重构和行为可塑性。这些数据表明，依赖于Ube2b的DNMT3a的降解解除了对CAMKK1基因的转录抑制，从而激活了CAMKK1/CaMKIα/βPIX/Rac1级联反应，导致药物诱导的肌动蛋白聚合和行为可塑性。
Compelling evidence suggests that synaptic structural plasticity, driven by remodeling of the actin cytoskeleton, underlies addictive drugs-induced long-lasting behavioral plasticity. However, the signaling mechanisms leading to actin cytoskeleton remodeling remain poorly defined. DNA methylation is a critical mechanism used to control activity-dependent gene expression essential for long-lasting synaptic plasticity. Here, we provide evidence that DNA methyltransferase DNMT3a is degraded by the E2 ubiquitin-conjugating enzyme Ube2b-mediated ubiquitination in dorsal hippocampus (DH) of rats that repeatedly self-administrated heroin. DNMT3a degradation leads to demethylation in CaMKK1 gene promotor, thereby facilitating CaMKK1 expression and consequent activation of its downstream target CaMKIα, an essential regulator of spinogenesis. CaMKK1/CaMKIα signaling regulates actin cytoskeleton remodeling in the DH and behavioral plasticity by activation of Rac1 via acting Rac guanine-nucleotide-exchange factor βPIX. These data suggest that Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on CaMKK1 gene and thus activates CaMKK1/CaMKIα/βPIX/Rac1 cascade, leading to drug use-induced actin polymerization and behavior plasticity.