The Regulation And Mechanism Of TRIM25 On Endoplasmic Reticulum Associated Protein Degradation

Recently,malignant tumors-induced death account for 3% of mortality every year in China.Malignant tumors have become a key factor threatening human health,so it is urgent for us to further explore the pathogenesis of malignant tumors for developing effective clinical treatment.ER stress(endoplasmic reticulum stress)known as a phenomenon that ER functions are disordered by some stimuli,such as hypoxia and nutrient deprivation,which often disrupts the cell microenvironment,leading to the accumulation of improperly folded proteins in ER.Particularly,solid tumor cells are usually exposed to such stress microenvironment,but they can maintain survival and normal functions.Because most of tumor cells have evolved stronger ability to cope with ER stress,they can restore ER homeostasis by promoting the elimination of improperly folded proteins and then create favorable conditions for their survival.ER stress can initiate the ERAD(endoplasmic reticulum associated protein degradation)which can help tumor cells eliminate the misfolded proteins in ER and maintain survival.ERAD plays an important role upon tumorigenesis,yet the mechanism of ERAD remained largely unknown.Therefore,our study is aimed at exploring the regulation and mechanism of ERAD to suggest some new potential markers and theoretical basis for cancer intervention.In the early stage of this study,we treated cells with TM and TG and found TRIM25(tripartite motif containing protein 25)was indeed increased upon ER stress,a member of TRIM family proteins.After that,we established the TRIM25 stable knockdown cell lines,applied molecular cloning,protein immunoblotting and flow cytometry methods to carry out experiments.To confirm the relationship between TRIM25 and ER stress,and further explore the regulatory and mechanism of TRIM25 on ERAD.Finally,the effect of TRIM25 on tumor growth in vivo was studied by nude mice tumor model.Our study showed that that TRIM25 is a novel inducible protein during ER stress,and as a feedback,it can negatively regulate ER stress.Under the condition of ER stress,TRIM25 can indirectly regulate ERAD response through Keap1/Nrf2 signaling pathway.It can reduce the protein stability of Keap1,promote Nrf2 into the nucleus,there by activate the antioxidant pathway and inhibit ROS levels and promote ERAD,which finally lead to tumors.In addition,the results of animal experiments show that TRIM25 knockdown can effectively inhibit the growth of tumor in vivo.Therefore,TRIM25 is an important protein regulating ERAD and expected to be a new target for tumor diagnosis and treatment.