Alzheimer’s disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70/Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70/Hsp90 machinery. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on Tau’s aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperone/substrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70/Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70/Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative diseases.

阿尔茨海默病是一种神经退行性疾病，其中病理修饰的 Tau 的错误折叠和聚集对于神经元功能障碍和变性至关重要。两个中心伴侣 Hsp70 和 Hsp90 协调蛋白质稳态，但 Tau 与 Hsp70/Hsp90 机器相互作用的性质仍然是个谜。在这里，我们表明 Tau 是人类 Hsp70/Hsp90 机器的高亲和力底物。复合物的形成涉及广泛的分子间接触，阻止 Tau 聚集并取决于 Tau 的易于聚集的重复区域。Hsp90 共伴侣 p23 直接结合 Tau 并稳定多伴侣/底物复合物，而 E3 泛素-蛋白连接酶 CHIP 有效地分解了靶向 Tau 以进行蛋白酶体降解的机制。