Beclin 1通过介导I型受体ALK5的再循环来调节神经元转化生长因子-β信号通路。
Beclin 1 regulates neuronal transforming growth factor-β signaling by mediating recycling of the type I receptor ALK5.
作者信息
O'Brien Caitlin E, Bonanno Liana, Zhang Hui, Wyss-Coray Tony
机构信息
Cell and Molecular Biology Program, Department of Biology, Stanford University, Stanford, CA, 94305, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
出版信息
Mol Neurodegener. 2015 Dec 21;10:69. doi: 10.1186/s13024-015-0065-0.
BACKGROUND
Beclin 1 is a key regulator of multiple trafficking pathways, including autophagy and receptor recycling in yeast and microglia. Decreased beclin 1 levels in the CNS result in neurodegeneration, an effect attributed to impaired autophagy. However, neurons also rely heavily on trophic factors, and signaling through these pathways requires the proper trafficking of trophic factor receptors.
RESULTS
We discovered that beclin 1 regulates signaling through the neuroprotective TGF-β pathway. Beclin 1 is required for recycling of the type I TGF-β receptor ALK5. We show that beclin 1 recruits the retromer to ALK5 and facilitates its localization to Rab11(+) endosomes. Decreased levels of beclin 1, or its binding partners VPS34 and UVRAG, impair TGF-β signaling.
CONCLUSIONS
These findings identify beclin 1 as a positive regulator of a trophic signaling pathway via receptor recycling, and suggest that neuronal death induced by decreased beclin 1 levels may also be due to impaired trophic factor signaling.
背景
Beclin 1是多种运输途径的关键调节因子，包括酵母和小胶质细胞中的自噬和受体循环利用。中枢神经系统中Beclin 1水平降低会导致神经退行性变，这种效应归因于自噬受损。然而，神经元也严重依赖营养因子，通过这些途径的信号传导需要营养因子受体的正确运输。
结果
我们发现Beclin 1通过神经保护TGF-β途径调节信号传导。I型TGF-β受体ALK5的循环利用需要Beclin 1。我们表明，Beclin 1将逆向转运蛋白募集到ALK5，并促进其定位于Rab11(+)内体。Beclin 1或其结合伙伴VPS34和UVRAG水平降低会损害TGF-β信号传导。
结论
这些发现确定Beclin 1是通过受体循环利用的营养信号途径的正向调节因子，并表明Beclin 1水平降低诱导的神经元死亡也可能归因于营养因子信号传导受损。
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