Molecular Mechanism And Pathological Function Underlying CGAS-STING Signaling-Triggered Cellular Senescence

Senescence is a cellular state with irreversible cell cycle arrest and specific secretory phenotype that contribute to various age-associated and degenerative diseases such as cancer.Further exploring the molecular mechanism of cellular senescence provides a new avenue for the treatment of related human diseases.p53-p21 and p16-RB signaling processes are key regulatory mechanisms underlying cellular senescence.DNA damage response activates and stabilizes the tumor suppressor p53,leading to the upregulation of p21 and p16 that inhibits cell cycle related kinases CDK2/4/6.Suppression of CDKs results in a hypo-phosphorylation and active state of RB,which associates with and inactivates the E2 F transcription factors in arresting cell cycle at the G1 to S checkpoint.Recently,an innate immune pathway that senses abnormal DNA,the c GAS-STING pathway,is reported to drive cellular senescence robustly.However,the underlying mechanism for STING-induced cellular senescence is still less known.Therefore,deciphering the molecular network resulting from c GAS-STING pathway might provide an intriguing probe to understand cellular senescence,a fundamental cellular process and a key player in human diseases.Based on the DNA damage-induced activation of c GAS-STING pathway and the loss of function analysis of cytogenetics,we found that IRF3,the key signal intermediary protein and transcription factor activated by c GAS-STING pathway,is critical in developing cellular senescence in various cell types.In terms of mechanism,IRF3,which is phosphorylated and activated by TBK1,enters the nucleus and forms an abundant endogenous complex with tumor suppressor RB,which prevents the formation of CDK4/6-cyclin-RB complex and inhibits hyperphosphorylation of RB.The hypo-phosphorylation keeps RB in the active state to bind E2 F transcription factors.The ternary complex of IRF3-RB-E2 F inhibits the expression of cell cycle related proteins driven by E2 F family proteins and causes cellular senescence.In the study of pathological function,cholestasis-induced liver fibrosis is used to analyze the physiological and pathological function of senescent hepatic stellate cells(HSCs).Analyses of the fibrotic model in IRF3 KO mice reveal a profound pathological role of this STING-IRF3-RB axis in senescent HSCs.Blocking the axis leads to a significant fibrosis phenotype,which can be well alleviated by CDK4/6 inhibitors.These innovative findings collectively highlight a straightforward mechanism of c GAS-STING-IRF3-RB pathway to drive cells into senescence and suggest a physiological function in restraining liver fibrosis.This study provides new theoretical and experimental basis for the progress of scientific cognition in the field of innate immune recognition and the exploration of new treatment strategies for liver fibrosis.In addition,I contributed the study to elucidate the regulation mechanism and function of protein phosphatase PPM1 A in Hippo-YAP pathway.Hippo-YAP pathway is an important signaling cascade that senses and responds to a variety of extracellular signals and regulates cell proliferation,organ size and regeneration.Our study proved that PPM1 A is the key physiological phosphatase of YAP,a transcription co-activator and key effector of Hippo-YAP pathway.Through some mouse disease models,we clarified the molecular mechanism,physiological and pathological function of PPM1 A in promoting organ regeneration after injury by dephosphorylating YAP.The study further improved the regulation mechanism and function of the key proteins in Hippo-YAP pathway.