葡萄糖调节的AXIN溶酶体膜转运的分子机制

葡萄糖是细胞最基本的供能和结构物质。我们之前阐明了低葡萄糖水平激活AMPK溶酶体途径，其中关键步骤是葡萄糖下降本身可直接作为信号分子促进AXIN转运到溶酶体膜上，AXIN上膜除了激活AMPK还能抑制mTORC1，从而引起合成代谢向分解代谢的转换。但是AXIN的转运的具体机制尚未明确。前期研究中，我们发现AXIN的转运是由v-ATPase介导的。该过程与AMPK的激活甚至于AMPK蛋白质本身并无关系，且对mTORC1调控的过程比AMPK对mTORC1的抑制更加直接和迅速，甚至于持续性定位在溶酶体上的AXIN片段能在AMPK不激活的情况下抑制mTORC1。本项目拟系统阐述AXIN的溶酶体膜转运的机制，同时研究AXIN如何通过mTORC1调节下游的糖脂代谢途径，并探索该过程在AMPK失活、mTORC1高活力的肿瘤中的功能，将对我们全面注释、阐明葡萄糖作为一种代谢信号的概念有着重要的意义。

Glucose is a fundamental source for both energy and building blocks. We have previously delineated a pathway by which glucose starvation leads to AMPK activation and meanwhile inhibition of mTORC1. This process involves a critical step where the scaffold protein AXIN was found to translocated onto the surface of the lysosome, resulting in the switch from anabolism to catabolism, suggesting that glucose, despite being an abundant nutrient molecule, is a regulatory signal for metabolic control. However, the detailed mechanism of how AXIN translocate to the lysosome remains unclear. Here, we found that the transportation of AXIN is mediated by the upstream v-ATPase of lysosomal pathway, independent of the activation of AMPK or even the AMPK protein itself. We also found that the AXIN translocation can facilitate the dissociation of mTORC1 from the lysosomal membrane, which exerts a more direct and rapid inhibition of mTORC1 than by AMPK. We have also generated an AXIN fragment (AXIN-NT) that is shown to be able to localize on the lysosomal membrane independent of glucose availability. AXIN-NT inhibits mTORC1 even if AMPK is not activated. We propose to study the detailed mechanisms of AXIN translocation and its biological function. Our findings will not only reveal the coordination mechanism of AMPK and mTORC1 on lysosomes and their regulation of metabolic processes, but also provide clues for the treatment of tumors characterized with inactivated AMPK and hyperactivated mTORC1.