Multilevel Regulations Of MTORC1 By AXIN Via The Lysosomal Pathway

Metabolism is the most fundamental and essential biological activity for any organism.The sensing systems inside monitor the availability of both nutrients and energy,and maintain its homeostasis through different metabolic regulatory pathways.Dysregulated metabolism causes a wide array of diseases.AMPK and mTORC1,two kinase complexes that control anabolic and catabolic processes,play critical roles in maintaining the metabolic homeostasis.Glucose is the most fundamental substance for structure and energy in cells.We have illustrated the activation process of AMPK in response to low glucose on the surface of the lysosome,which has now been referred to as the AMPK lysosomal pathway.During this process,the key step is that aldolase,when unoccupied by its substrate fructose-1,6-bisphosphate(FBP)as a result of low glucose,can initiate the translocation of AXIN to lysosomal membrane.The translocation of AXIN in complex with LKB1 activates AMPK,and inhibits mTORC1 on lysosome,which subsequently switches from anabolism of organism into catabolism.However,the detailed mechanism of the AXIN translocation is still unclear.In this dissertation,I uncovered that the AXIN translocation is mediated by the lysosomal v-ATPase;importantly,the translocation process is independent of AMPK activation,even the AMPK protein itself.We also found that the AXIN-dependent and AMPK-independent inhibition of mTORC1 is more direct and more quickly than the process via activated AMPK.In addition,an AXIN N-terminal fragment,which can be constitutively located on lysosome,also inhibits mTORC1 in the absence of AMPK.In summary,we have partially uncovered the mechanism of how AXIN participates in the regulation of AMPK and mTORC1.Our findings will not only reveal the mechanism for the coordinated regulation of AMPK and mTORC1 on the lysosome in response to low glucose,but also provide clues for the treatment of metabolic diseases and perhaps cancer alike.