PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation.
PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation.
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DOI：
10.1126/scisignal.2005191
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发表时间：
2014-11-04
影响因子：
7.3
通讯作者：
Rameh LE
中科院分区：
文献类型：
--
作者：
Mackey AM;Sarkes DA;Bettencourt I;Asara JM;Rameh LE
磷脂酰肌醇-5-磷酸4激酶（PIP4ks）是一类脂质激酶，专门以磷脂酰肌醇5-磷酸（PI-5-P）为底物合成磷脂酰肌醇4,5-二磷酸（pi -4,5- p2）。在果蝇中，PIP4k功能的抑制导致细胞变小和雷帕霉素复合物1 （TORC1）信号传导靶标降低。在这里，我们发现PIP4k的γ亚型通过哺乳动物TORC1 （mTORC1）刺激信号传导。在mTORC1因Tsc2缺乏而组成性激活的细胞中，PIP4kγ的敲低会减少细胞质量。在Tsc2空细胞中，mTORC1的激活部分独立于氨基酸或葡萄糖和谷氨酰胺。PIP4kγ敲低抑制Tsc2敲低细胞中mTORC1的营养非依赖性激活，并降低野生型细胞中的基础mTORC1信号传导。PIP4kγ被mTORC1磷酸化并与该复合物相关。磷酸化的PIP4kγ在轻微粒体囊泡中富集，而未磷酸化的PIP4kγ在与高尔基体相关的重微粒体囊泡中富集。此外，基础mTORC1信号通过过表达未磷酸化的野生型PIP4kγ或磷酸化缺陷突变体而增强，并通过过表达磷酸化模拟突变体而减弱。总之，这些结果表明，PIP4kγ和mTORC1在一个自我调节的反馈回路中相互作用，以维持饥饿期间低水平和严格调节的mTORC1激活。
Phosphatidylinositol-5-phosphate 4-kinases (PIP4ks) are a family of lipid kinases that specifically use phosphatidylinositol 5-phosphate (PI-5-P) as a substrate to synthesize phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2). Suppression of PIP4k function in Drosophila results in smaller cells and reduced target of rapamycin complex 1 (TORC1) signaling. Here we showed that the γ isoform of PIP4k stimulated signaling through mammalian TORC1 (mTORC1). Knockdown of PIP4kγ reduced cell mass in cells in which mTORC1 is constitutively activated by Tsc2 deficiency. In Tsc2 null cells mTORC1 activation was partially independent of amino acids or glucose and glutamine. PIP4kγ knockdown inhibited the nutrient-independent activation of mTORC1 in Tsc2 knockdown cells and reduced basal mTORC1 signaling in wild-type cells. PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi. Furthermore, basal mTORC1 signaling was enhanced by overexpression of unphosphorylated wild-type PIP4kγ or a phosphorylation-defective mutant and decreased by overexpression of a phosphorylation mimetic mutant. Together these results demonstrate that PIP4kγ and mTORC1 interact in a self-regulated feedback loop to maintain low and tightly regulated mTORC1 activation during starvation.