Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Signature Research Program in Neuroscience and Behavior Disorders, Duke NUS Graduate Medical School Singapore, 8 College Road, Level 05-29, Singapore 169857, Singapore.
Neuron. 2014 Jun 18;82(6):1299-316. doi: 10.1016/j.neuron.2014.05.016.
Activity-dependent gene transcription and protein synthesis underlie many forms of learning-related synaptic plasticity. At excitatory glutamatergic synapses, the immediate early gene product Arc/Arg3.1 couples synaptic activity to postsynaptic endocytosis of AMPA-type glutamate receptors. Although the mechanisms for Arc induction have been described, little is known regarding the molecular machinery that terminates Arc function. Here, we demonstrate that the RING domain ubiquitin ligase Triad3A/RNF216 ubiquitinates Arc, resulting in its rapid proteasomal degradation. Triad3A associates with Arc, localizes to clathrin-coated pits, and is associated with endocytic sites in dendrites and spines. In the absence of Triad3A, Arc accumulates, leading to the loss of surface AMPA receptors. Furthermore, loss of Triad3A mimics and occludes Arc-dependent forms of synaptic plasticity. Thus, degradation of Arc by clathrin-localized Triad3A regulates the availability of synaptic AMPA receptors and temporally tunes Arc-mediated plasticity at glutamatergic synapses.
活动依赖性基因转录和蛋白质合成是许多形式的学习相关突触可塑性的基础。在兴奋性谷氨酸能突触中，即时早期基因产物 Arc/Arg3.1 将突触活动与 AMPA 型谷氨酸受体的突触后内吞作用偶联。虽然已经描述了 Arc 诱导的机制，但对于终止 Arc 功能的分子机制知之甚少。在这里，我们证明 RING 结构域泛素连接酶 Triad3A/RNF216 泛素化 Arc，导致其迅速被蛋白酶体降解。Triad3A 与 Arc 结合，定位于网格蛋白包被的陷窝，并与树突和棘突中的内吞部位相关。在缺乏 Triad3A 的情况下，Arc 积累，导致表面 AMPA 受体丧失。此外，Triad3A 的缺失模拟并阻断了 Arc 依赖性突触可塑性。因此，网格蛋白定位的 Triad3A 通过降解 Arc 调节突触 AMPA 受体的可用性，并在谷氨酸能突触上对 Arc 介导的可塑性进行时间调节。
