FKBP38介导氨基酸信号驱动mTORC1定位于溶酶体表面并促进乳蛋白合成的机制

牛奶由奶牛乳腺上皮细胞分泌，限制性氨基酸影响奶牛乳蛋白合成和泌乳。mTORC1可以感受细胞内氨基酸信号锚定于溶酶体表面并被激活。近年发现氨基酸驱动mTORC1定位于溶酶体表面激活过程有多种蛋白分子的参与，但相互之间的关系还不清楚。FKBP38 具有结合蛋白特性，可能是mTORC1的内源性抑制蛋白，Rheb和p62锚定于溶酶体表面，连接mTORC1并激活它。我们前期研究发现FKBP38可与p62、Rheb发生直接的相互作用，文献亦显示三者都与氨基酸信号有关，由此推测这种相互作用可能会影响mTORC1定位于溶酶体表面。本项目拟以奶牛乳腺上皮细胞为模型，通过分子细胞生物学技术验证FKBP38介导奶牛泌乳相关限制性氨基酸信号，驱动mTORC1定位于溶酶体表面激活并促进乳蛋白合成。进一步利用蛋白质组学技术探讨几种限制性氨基酸可能的胞内感受器。

Milk is secreted by the cow mammary epithelial cells, and the limited amino acids affect protein synthesis and lactation of cow. mTORC1 can sense intracellular amino acid signaling and translocate to the surface of lysosome, and was activated. In recent years, it has been found that multiple protein molecules participate the process of the mTORC1 localizes to lysosomal surface and be activated by amino acid signal, but the relationship between the involved proteins is unclear. FKBP38 has the characteristics of binding protein, and may be an endogenous inhibitor of mTORC1. Rheb and p62 are the proteins that anchored to the surface of lysosomes, and can link to mTORC1 to activate it. Our previous study found that FKBP38 interacts directly with p62 and Rheb, and the literatures also showed that all three are related to amino acid signals, suggesting that this interaction may affect the localization of mTORC1 on lysosomes surface. This project intends to use the cow mammary epithelial cells as a model to verify the mechanism that FKBP38 mediates signals of the lactation-related limited amino acids, which drives mTORC1 to localize on lysosomal surface and promote milk protein synthesis, with molecular cell biology techniques. Further, possible intracellular sensors for the several kinds of limited amino acids will be explored by proteomics methods.