Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, 110016, India.
Cell Commun Signal. 2023 Apr 21;21(1):82. doi: 10.1186/s12964-023-01071-x.
PP1γ is one of the isoforms of catalytic subunit of a Ser/Thr phosphatase PP1. The role of PP1γ in cellular regulation is largely unknown. The present study investigated the role of PP1γ in regulating neuronal insulin signaling and insulin resistance in neuronal cells. PP1 was inhibited in mouse neuroblastoma cells (N2a) and human neuroblastoma cells (SH-SY5Y). The expression of PP1α and PP1γ was determined in insulin resistant N2a, SH-SY5Y cells and in high-fat-diet-fed-diabetic mice whole-brain-lysates. PP1α and PP1γ were silenced by siRNA in N2a and SH-SY5Y cells and effect was tested on AKT isoforms, AS160 and GSK3 isoforms using western immunoblot, GLUT4 translocation by confocal microscopy and glucose uptake by fluorescence-based assay.
Results showed that, in one hand PP1γ, and not PP1α, regulates neuronal insulin signaling and insulin resistance by regulating phosphorylation of AKT2 via AKT2-AS160-GLUT4 axis. On the other hand, PP1γ regulates phosphorylation of GSK3β via AKT2 while phosphorylation of GSK3α via MLK3. Imbalance in this regulation results into AD-like phenotype.
PP1γ acts as a linker, regulating two pathophysiological conditions, neuronal insulin resistance and AD. Video Abstract.
PP1γ 是丝氨酸/苏氨酸磷酸酶 PP1 的催化亚基同工型之一。PP1γ 在细胞调节中的作用在很大程度上是未知的。本研究旨在探讨 PP1γ 在调节神经元胰岛素信号和神经元细胞胰岛素抵抗中的作用。在小鼠神经母细胞瘤细胞（N2a）和人神经母细胞瘤细胞（SH-SY5Y）中抑制了 PP1。在胰岛素抵抗的 N2a、SH-SY5Y 细胞和高脂肪饮食喂养的糖尿病小鼠全脑裂解物中测定了 PP1α 和 PP1γ 的表达。通过 siRNA 在 N2a 和 SH-SY5Y 细胞中沉默 PP1α 和 PP1γ，并通过 Western 免疫印迹检测 AKT 同工型、AS160 和 GSK3 同工型的影响，通过共聚焦显微镜检测 GLUT4 易位，通过荧光测定法检测葡萄糖摄取。
结果表明，一方面，PP1γ 通过 AKT2-AS160-GLUT4 轴调节 AKT2 的磷酸化来调节神经元胰岛素信号和胰岛素抵抗，而不是 PP1α。另一方面，PP1γ 通过 AKT2 调节 GSK3β 的磷酸化，而通过 MLK3 调节 GSK3α 的磷酸化。这种调节的不平衡导致 AD 样表型。
PP1γ 作为一种连接物，调节两种病理生理状况，即神经元胰岛素抵抗和 AD。视频摘要。
Zotero 插件
