BAG5促进α-突触核蛋白寡聚体形成并与自噬衔接蛋白p62发生功能相互作用。
BAG5 Promotes Alpha-Synuclein Oligomer Formation and Functionally Interacts With the Autophagy Adaptor Protein p62.
作者信息
Friesen Erik L, Zhang Yu Tong, Earnshaw Rebecca, De Snoo Mitch L, O'Hara Darren M, Agapova Victoria, Chau Hien, Ngana Sophie, Chen Kevin S, Kalia Lorraine V, Kalia Suneil K
机构信息
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada.
出版信息
Front Cell Dev Biol. 2020 Aug 4;8:716. doi: 10.3389/fcell.2020.00716. eCollection 2020.
Molecular chaperones are critical to maintaining intracellular proteostasis and have been shown to have a protective role against alpha-synuclein-mediated toxicity. Co-chaperone proteins regulate the activity of molecular chaperones and connect the chaperone network to protein degradation and cell death pathways. Bcl-2 associated athanogene 5 (BAG5) is a co-chaperone that modulates proteostasis by inhibiting the activity of Heat shock protein 70 (Hsp70) and several E3 ubiquitin ligases, resulting in enhanced neurodegeneration in models of Parkinson's disease (PD). Here we identify a novel interaction between BAG5 and p62/sequestosome-1 (SQSTM1), suggesting that BAG5 may bridge the chaperone network to autophagy-mediated protein degradation. We found that BAG5 enhanced the formation of pathogenic alpha-synuclein oligomers and regulated the levels and subcellular distribution of p62. These results extend the role of BAG5 in alpha-synuclein processing and intracellular proteostasis.
分子伴侣对于维持细胞内蛋白质稳态至关重要，并且已被证明对α-突触核蛋白介导的毒性具有保护作用。共伴侣蛋白调节分子伴侣的活性，并将伴侣网络与蛋白质降解和细胞死亡途径相连。Bcl-2相关抗凋亡蛋白5（BAG5）是一种共伴侣蛋白，它通过抑制热休克蛋白70（Hsp70）和几种E3泛素连接酶的活性来调节蛋白质稳态，从而在帕金森病（PD）模型中导致神经退行性变增强。在此，我们鉴定出BAG5与p62/聚集体蛋白1（SQSTM1）之间存在一种新的相互作用，提示BAG5可能将伴侣网络与自噬介导的蛋白质降解联系起来。我们发现BAG5增强了致病性α-突触核蛋白寡聚体的形成，并调节了p62的水平和亚细胞分布。这些结果扩展了BAG5在α-突触核蛋白加工和细胞内蛋白质稳态中的作用。
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