The Jackson Laboratory, Bar Harbor, ME, USA.
The Jackson Laboratory, Bar Harbor, ME, USA Graduate Programs, Department of Molecular & Biomedical Sciences, The University of Maine, Orono, ME, USA.
EMBO J. 2015 Feb 3;34(3):275-93. doi: 10.15252/embj.201489062. Epub 2014 Nov 25.
Numerous extrinsic and intrinsic insults trigger the HSF1-mediated proteotoxic stress response (PSR), an ancient transcriptional program that is essential to proteostasis and survival under such conditions. In contrast to its well-recognized mobilization by proteotoxic stress, little is known about how this powerful adaptive mechanism reacts to other stresses. Surprisingly, we discovered that metabolic stress suppresses the PSR. This suppression is largely mediated through the central metabolic sensor AMPK, which physically interacts with and phosphorylates HSF1 at Ser121. Through AMPK activation, metabolic stress represses HSF1, rendering cells vulnerable to proteotoxic stress. Conversely, proteotoxic stress inactivates AMPK and thereby interferes with the metabolic stress response. Importantly, metformin, a metabolic stressor and popular anti-diabetic drug, inactivates HSF1 and provokes proteotoxic stress within tumor cells, thereby impeding tumor growth. Thus, these findings uncover a novel interplay between the metabolic stress sensor AMPK and the proteotoxic stress sensor HSF1 that profoundly impacts stress resistance, proteostasis, and malignant growth.
许多外在和内在的损伤会触发 HSF1 介导的蛋白毒性应激反应（PSR），这是一种古老的转录程序，对于在这种条件下维持蛋白稳态和生存至关重要。与人们熟知的其被蛋白毒性应激所调动不同，人们对这种强大的适应性机制如何应对其他应激知之甚少。令人惊讶的是，我们发现代谢应激会抑制 PSR。这种抑制在很大程度上是通过中央代谢传感器 AMPK 介导的，AMPK 与 HSF1 相互作用，并在 Ser121 位点磷酸化 HSF1。通过 AMPK 的激活，代谢应激会抑制 HSF1，使细胞易受蛋白毒性应激的影响。相反，蛋白毒性应激会使 AMPK 失活，从而干扰代谢应激反应。重要的是，二甲双胍是一种代谢应激源和常用的抗糖尿病药物，它会使 HSF1 失活，并在肿瘤细胞内引发蛋白毒性应激，从而阻碍肿瘤生长。因此，这些发现揭示了代谢应激传感器 AMPK 和蛋白毒性应激传感器 HSF1 之间的一种新的相互作用，这种相互作用对抵抗应激、蛋白稳态和恶性生长有深远影响。
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