PI31 Is an Adaptor Protein for Proteasome Transport in Axons and Required for Synaptic Development
PI31 Is an Adaptor Protein for Proteasome Transport in Axons and Required for Synaptic Development
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DOI：
10.1016/j.devcel.2019.06.009
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发表时间：
2019-08-19
影响因子：
11.8
通讯作者：
Steller, Hermann
中科院分区：
文献类型：
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作者：
Liu, Kai;Jones, Sandra;Steller, Hermann
泛素蛋白酶体系统的蛋白质降解对于神经元功能至关重要。神经元利用微管依赖性分子马达将蛋白酶体分配给突触，但蛋白酶体如何与马达耦合以及如何对其进行调节以满足不断变化的蛋白质分解需求仍然很大程度上未知。我们证明保守的蛋白酶体结合蛋白 PI31 作为适配器将蛋白酶体与动力蛋白轻链蛋白 (DYNLL1/2) 偶联。 PI31 失活会抑制轴突中的蛋白酶体运动，并破坏突触蛋白质稳态、结构和功能。此外，p38 MAPK 对 PI31 的磷酸化增强了与 DYNLL1/2 的结合，并促进了轴突中蛋白酶体的定向运动，这表明了一种调节蛋白酶体加载到马达上的机制。小鼠神经元中 PI31 的失活减弱了轴突中蛋白酶体的运动，表明该过程是保守的。由于影响 PI31 活性的突变与人类神经退行性疾病相关，因此 PI31 介导的蛋白酶体轴突运输受损可能会导致这些疾病。
Protein degradation by the ubiquitin-proteasome system is critical for neuronal function. Neurons utilize microtubule-dependent molecular motors to allocate proteasomes to synapses, but how proteasomes are coupled to motors and how this is regulated to meet changing demand for protein breakdown remain largely unknown. We show that the conserved proteasome-binding protein PI31 serves as an adaptor to couple proteasomes with dynein light chain proteins (DYNLL1/2). The inactivation of PI31 inhibited proteasome motility in axons and disrupted synaptic proteostasis, structure, and function. Moreover, phosphorylation of PI31 by p38 MAPK enhanced binding to DYNLL1/2 and promoted the directional movement of proteasomes in axons, suggesting a mechanism to regulate loading of proteasomes onto motors. Inactivation of PI31 in mouse neurons attenuated proteasome movement in axons, indicating this process is conserved. Because mutations affecting PI31 activity are associated with human neurodegenerative diseases, impairment of PI31-mediated axonal transport of proteasomes may contribute to these disorders.