| Biological evolution is long,and complex,it won’t depart from the original aim or stand.From organism to cell,uptaking external nutrients is the essential life activities for both of them,and is also one of the important characteristics of life.In terms of the eell,intaking nutrients means it must have a set of sensitive nutrient sensing system,and in this system,the core position of the mTORCl signal pathway is irreplaceable.As a key linker between nutrition and cell status,mTORCl mainly regulates protein translation,fat synthesis,cell autophagy,cell proliferation and other physiological processes.Activation of mTORCl signaling pathway has been the focus for years,but its specific activation mechanism remains to be explored.Rheb,a small G protein,is a key protein in the process of growth factor activating mTORCl.Besides,Rheb is a member of the Ras family,acts as a direct activator of mTORCl.TSC complex(TSC1/2/TBClD7)is the most important negative regulator of Rheb activity.As a GAP of Rheb,TSC can promote the conversion of Rheb-GTP to Rheb-GDP,thereby inhibiting the activity of Rheb.But so far,the regulatory protein of Rheb still needs to be identified.Although our previous studies have shown that Rheb can be modified by ubiquitin,it is not clear how it is going to be deubiquitinated.In this article,we found the de-ubiquitin conjugating enzyme USP4 can specifically interact with Rheb,remove its ubiquitin modification,reduce the interaction between Rheb and TSC2 and consequently active the GTPase of Rheb.In addition,we also found that USP4 can positively regulate mTORCl signaling pathway,inhibit autophagy and promote cell proliferation.This study deepens the understanding of the mechanism of mTORCl signaling pathway and provides new strategies and targets for the treatment of metabolic diseases and tumors. |
