Dite Toby A, Ling Naomi X Y, Scott John W, Hoque Ashfaqul, Galic Sandra, Parker Benjamin L, Ngoei Kevin R W, Langendorf Christopher G, O'Brien Matthew T, Kundu Mondira, Viollet Benoit, Steinberg Gregory R, Sakamoto Kei, Kemp Bruce E, Oakhill Jonathan S
Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia.
Protein Chemistry & Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia.
Nat Commun. 2017 Sep 18;8(1):571. doi: 10.1038/s41467-017-00628-y.
AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for maintaining cellular energy homeostasis. Activation of AMPK by salicylate and the thienopyridone A-769662 is critically dependent on phosphorylation of Ser108 in the β1 regulatory subunit. Here, we show a possible role for Ser108 phosphorylation in cell cycle regulation and promotion of pro-survival pathways in response to energy stress. We identify the autophagy initiator Unc-51-like kinase 1 (ULK1) as a β1-Ser108 kinase in cells. Cellular β1-Ser108 phosphorylation by ULK1 was dependent on AMPK β-subunit myristoylation, metabolic stress associated with elevated AMP/ATP ratio, and the intrinsic energy sensing capacity of AMPK; features consistent with an AMP-induced myristoyl switch mechanism. We further demonstrate cellular AMPK signaling independent of activation loop Thr172 phosphorylation, providing potential insight into physiological roles for Ser108 phosphorylation. These findings uncover new mechanisms by which AMPK could potentially maintain cellular energy homeostasis independently of Thr172 phosphorylation.AMPK is involved in sensing of metabolic stress. The authors show that the autophagy initiator ULK1 phosphorylates β1-Ser108 on the regulatory β1-subunit, sensitizing AMPK to allosteric drugs, and activates signaling pathways that appear independent of Thr172 phosphorylation in the kinase activation loop.
AMP激活的蛋白激酶（AMPK）是一种代谢应激感应酶，负责维持细胞能量稳态。水杨酸盐和噻吩并吡啶A-769662对AMPK的激活严重依赖于β1调节亚基中Ser108的磷酸化。在此，我们展示了Ser108磷酸化在细胞周期调控以及响应能量应激促进促生存途径中的可能作用。我们确定自噬起始因子Unc-51样激酶1（ULK1）为细胞中的β1-Ser108激酶。ULK1介导的细胞β1-Ser108磷酸化依赖于AMPKβ亚基的肉豆蔻酰化、与AMP/ATP比值升高相关的代谢应激以及AMPK的内在能量感应能力；这些特征与AMP诱导的肉豆蔻酰开关机制一致。我们进一步证明细胞AMPK信号传导独立于激活环Thr172磷酸化，这为Ser108磷酸化的生理作用提供了潜在见解。这些发现揭示了AMPK可能独立于Thr172磷酸化维持细胞能量稳态的新机制。AMPK参与代谢应激的感应。作者表明，自噬起始因子ULK1使调节性β1亚基上的β1-Ser108磷酸化，使AMPK对变构药物敏感，并激活似乎独立于激酶激活环中Thr172磷酸化的信号通路。
