ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation
ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation
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DOI：
10.1038/ncb2373
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发表时间：
2011-12-01
影响因子：
21.3
通讯作者：
Araki, Toshiyuki
中科院分区：
文献类型：
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作者：
Wakatsuki, Shuji;Saitoh, Fuminori;Araki, Toshiyuki
沃勒变性在许多神经系统疾病中都能观察到，因此阐明轴突变性机制对于预防此类疾病以及进一步开发治疗方法至关重要。泛素蛋白酶体系统（UPS）与沃勒变性有关，但其潜在的分子机制仍不清楚。在此我们表明，E3连接酶ZNRF1通过将AKT作为靶点经UPS降解来促进沃勒变性。AKT使糖原合成酶激酶 - 3β（GSK3B）磷酸化，从而使其在轴突中失活。AKT的过表达显著延迟轴突变性。GSK3B的活性（非磷酸化）形式的过表达诱导CRMP2磷酸化，这是在变性轴突中观察到的微管重组所必需的。抑制GSK3B以及非磷酸化CRMP2的过表达都能保护轴突免受沃勒变性。这些发现表明ZNRF1 - AKT - GSK3B - CRMP2通路在控制沃勒变性中起重要作用。
Wallerian degeneration is observed in many neurological disorders, and it is therefore important to elucidate the axonal degeneration mechanism to prevent, and further develop treatment for, such diseases. The ubiquitin proteasome system (UPS) has been implicated in Wallerian degeneration, but the underlying molecular mechanism remains unclear. Here we show that ZNRF1, an E3 ligase, promotes Wallerian degeneration by targeting AKT to degrade through the UPS. AKT phosphorylates glycogen synthase kinase-3 beta (GSK3B), and thereby inactivates it in axons. AKT overexpression significantly delays axonal degeneration. Overexpression of the active (non-phosphorylated) form of GSK3B induces CRMP2 phosphorylation, which is required for the microtubule reorganization observed in the degenerating axon. The inhibition of GSK3B and the overexpression of non-phosphorylated CRMP2 both protected axons from Wallerian degeneration. These findings indicate that the ZNRF1 AKT GSK3B CRMP2 pathway plays an important role in controlling Wallerian degeneration.