Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer’s disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

伴侣介导的自噬 (CMA) 是一种依赖溶酶体的选择性降解途径，与癌症和神经退行性疾病的发病机制有关。然而，调节 CMA 的机制尚不完全清楚。在这里，使用公正的药物筛选方法，我们发现二甲双胍，一种通常是第一种用于 2 型糖尿病的药物，可以诱发 CMA。我们描述了二甲双胍诱导 CMA 的机制是通过激活 TAK1-IKKα/β 信号传导导致 CMA 的关键介质 Hsc70 的 Ser85 磷酸化及其激活。值得注意的是，我们发现β淀粉样蛋白前体蛋白（APP）是一种CMA底物，它以IKKα/β依赖性方式与Hsc70结合。抑制 CMA 介导的 APP 降解增强了其细胞毒性。重要的，我们发现，在阿尔茨海默病 (AD) 的 APP/PS1 小鼠模型中，Hsc70 过表达或二甲双胍激活 CMA 可有效降低累积的脑 Aβ 斑块水平并逆转分子和行为 AD 表型。我们的研究阐明了一种通过二甲双胍-TAK1-IKKα/β-Hsc70 信号传导调节 CMA 的新机制，并表明二甲双胍是一种新的 CMA 激活剂，用于治疗 AD 等疾病，这种治疗干预可能是有益的。