Molecular Delineation Of Resveratrol-elicited LKB1-Sirt1 Signaling In Cell Plasticity Control

Liver Kinase B1(LKB1),also known as STK11,is a serine/threonine that function as a critical cancer suppressor in many cancer cells.LKB1 is a master upstream kinase of 13 AMP-activated protein kinase(AMPK)-related protein kinases,and possesses various biological functions.The physiological roles of LKB1 is mainly achieved by activating downstream substrates in the form of phosphorylation modification.However,the mechanism of activity regulation of LKB1 itself under various cellular stress and new functional regulation involved of LKB1 are not clear.Taking advance of bioinformatics and mass spectrometry tools,we identified deacetylase Sirtl is a new substrate of LKB1.In mammalian cells,the Sirtuin family consists of seven proteins,Sirt1-Sirt7.Sirtl is the closest mammalian ortholog of yeast Sir2,which has been studied much more than other family members.Originally,studies on the function of Sirtl focused on the regulation of gene transcriptional silencing and DNA damage repair.Later researches found that Sirtl also plays important roles in other cellular processes,including stress response,inflammatory response,mitochondrial function.During this period,many factors affecting Sirt1 activity has been found,such as NAD+cofactor,DBC1 inhibitor,AROS activator,etc.Depending on mechanisms regulating Sirtl activity,these factors can be classified into two categories:regulating affinity between substrates and Sirtl deacetylase core domain and affecting interaction between C terminal and deacetylase core domain of Sirt1.Our study found that LKB1 dependent phosphorylation of Sirtl promoted the binding of C terminal with deacetylase core domain and activated Sirt1.Meanwhile,we found that LKB1-Sirtl signaling pathway could respond to the stimulation of resveratrol.Resveratrol is a kind of natural polyphenols,which is widely found in grape,peanut,mulberry and other plants.It is a stress response factor produced by plants.Resveratrol firstly attracted extensive scientific attention due to its remarkable functions in the benefits of cardiovascular diseases and was subsequently found to possess potent antitumor activity.Later,studies have found that resveratrol is a highly effective activator of Sirtl,and the physiological functions of resveratrol are mainly mediated by Sirt1.However,the mechanisms of resveratrol activating Sirtl is not clear,and the debate is still existed.Our study found that LKB1 can activate Sirtl by phosphorylating the C terminal of Sirtl,which promoting the binding of the C terminal and deacetylase core domain in the stimulation of resveratrol.Activated Sirtl mediates the transcription of genes related to mitochondria respiration and proliferation through deacetylation and activation of transcription factor peroxisome proliferator-activated receptor y coactivator PGC-1α.In conclusion,our study revealed the mechanism of the Sirtl activation in the regulation of mitochondrial function mediated by resveratrol,providing hints for the interpretation of pharmacological effects of resveratrol.