mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate
mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate
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DOI：
10.1126/science.aaf8310
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发表时间：
2017-06-02
期刊：
影响因子：
56.9
通讯作者：
Haucke, Volker
中科院分区：
文献类型：
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作者：
Marat, Andrea L.;Wallroth, Alexander;Haucke, Volker
通过溶酶体和晚期内涵体 (LyLE) 上的雷帕霉素复合物 1 (mTORC1) 的机械靶点进行营养感应，调节细胞生长。许多因素刺激 mTORC1 活性，包括质膜上 I 类磷脂酰肌醇 3-激酶 (PI3K) 产生磷脂酰肌醇 3,4,5-三磷酸 [PI(3,4,5)P-3]。我们研究了生长因子剥夺条件下抑制 mTORC1 的机制。我们鉴定出磷脂酰肌醇 3,4-二磷酸 [PI(3,4)P-2]，由 LyLE 处的 II 类 PI3K beta (PI3KC2 beta) 合成，作为 mTORC1 的负调节因子，而 PI3KC2 beta 的缺失会使 mTORC1 过度激活。生长因子剥夺诱导 PI3KC2 beta 与 mTORC1 的 Raptor 亚基关联。局部 PI(3,4) P2 合成通过 Raptor 与抑制性 14-3-3 蛋白的结合触发 mTORC1 活性的抑制。这些结果揭示了局部 PI(3,4)P-2 产生在关闭 mTORC1 中的意外功能。
Nutrient sensing by mechanistic target of rapamycin complex 1 (mTORC1) on lysosomes and late endosomes (LyLEs) regulates cell growth. Many factors stimulate mTORC1 activity, including the production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P-3] by class I phosphatidylinositol 3-kinases (PI3Ks) at the plasma membrane. We investigated mechanisms that repress mTORC1 under conditions of growth factor deprivation. We identified phosphatidylinositol 3,4-bisphosphate [PI(3,4)P-2], synthesized by class II PI3K beta (PI3KC2 beta) at LyLEs, as a negative regulator of mTORC1, whereas loss of PI3KC2 beta hyperactivated mTORC1. Growth factor deprivation induced the association of PI3KC2 beta with the Raptor subunit of mTORC1. Local PI(3,4) P2 synthesis triggered repression of mTORC1 activity through association of Raptor with inhibitory 14-3-3 proteins. These results unravel an unexpected function for local PI(3,4)P-2 production in shutting off mTORC1.