The Protein Phosphatase 1 Complex Is a Direct Target of AKT that Links Insulin Signaling to Hepatic Glycogen Deposition
The Protein Phosphatase 1 Complex Is a Direct Target of AKT that Links Insulin Signaling to Hepatic Glycogen Deposition
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蛋白磷酸酶 1 复合物是 AKT 的直接靶标，它将胰岛素信号转导与肝糖原沉积联系起来
DOI：
10.1016/j.celrep.2019.08.066
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发表时间：
2019-09-24
期刊：
影响因子：
8.8
通讯作者：
Li, Peng
中科院分区：
文献类型：
--
作者：
Li, Qiqi;Zhao, Qiuye;Li, Peng
胰岛素刺激的肝糖原合成对于葡萄糖稳态至关重要。在这里，我们发现 PPP1R3G（蛋白磷酸酶 1 (PP1) 的调节亚基）直接被 AKT 磷酸化。 PPP1R3G 磷酸化随着禁食-再进食周期而波动，并且是胰岛素刺激的去磷酸化所必需的，即肝细胞中糖原合酶 (GS) 的激活。在这项研究中，我们证明 PPP1R3G 的敲低可显着抑制胰岛素反应。野生型 PPP1R3G（而非磷酸化缺陷突变体）的引入增加了体内肝糖原沉积、血糖清除率和胰岛素敏感性。从机制上讲，磷酸化的 PPP1R3G 显示出与磷酸-GS 的结合增加，并促进磷酸-GS 的去磷酸化。此外，PP1 的另一个调节亚基 PPP1R3B 与去磷酸化的 GS 结合，从而将胰岛素刺激转变成肝糖原沉积。重要的是，这种 PP1 介导的信号级联独立于 GSK3。因此，我们揭示了由胰岛素/AKT/PPP1R3G/PPP1R3B组成的调节轴，其与GSK3依赖性途径平行运作，控制胰岛素信号传导中的糖原合成和葡萄糖稳态。
Insulin-stimulated hepatic glycogen synthesis is central to glucose homeostasis. Here, we show that PPP1R3G, a regulatory subunit of protein phosphatase 1 (PP1), is directly phosphorylated by AKT. PPP1R3G phosphorylation fluctuates with fasting-refeeding cycle and is required for insulin-stimulated dephosphorylation, i.e., activation of glycogen synthase (GS) in hepatocytes. In this study, we demonstrate that knockdown of PPP1R3G significantly inhibits insulin response. The introduction of wildtype PPP1R3G, and not phosphorylation-defective mutants, increases hepatic glycogen deposition, bloodglucose clearance, and insulin sensitivity in vivo. Mechanistically, phosphorylated PPP1R3G displays increased binding for, and promotes dephosphorylation of, phospho-GS. Furthermore, PPP1R3B, another regulatory subunit of PP1, binds to the dephosphorylated GS, thereby relaying insulin stimulation to hepatic glycogen deposition. Importantly, this PP1-mediated signaling cascade is independent of GSK3. Therefore, we reveal a regulatory axis consisting of insulin/AKT/PPP1R3G/PPP1R3B that operates in parallel to the GSK3-dependent pathway, controlling glycogen synthesis and glucose homeostasis in insulin signaling.