Deubiquitinating Enzyme USP7 Regulates Aging In Drosophila By Ubiquitination And Autophagy

Aging is an inevitable biological phenomenon characterized by a gradual loss of the physiological integrity of the body,which leads to impaired cellular functions.With aging,the incidence of many aging-related diseases begins to increase.It is necessary to conduct an in-depth study on the mechanism of aging,so that can lay the foundation for aging and anti-aging research.The Ubiquitin-Specific Protease7(USP7)is a deubiquitinating enzyme,it has been reported that USP7 has many biological functions: including involvement in the development of tumor cancer through the p53 pathway,cell cycle process,and DNA repair.As a deubiquitinase USP7 remove substrate ubiquitination and participate in maintaining proteostasis.However,the role of USP7 in aging research and its regulatory mechanisms are still unclear.The loss of protein homeostasis is one of the hallmarks of aging,In order to explore the regulation mechanism of USP7 in the aging process,we used Drosophila as a model animal to carry out relevant experiments.The main results are as follows:1.Knock-down the expression of dusp7 gene in the whole body or intestine can significantly shorten the lifespan of Drosophila.The lifespan of the whole body knock-down the dusp7 is shortened by 28.9%,and the lifespan of the intestinal knock-down dusp7 is shortened by 13.3%.After knock-down the dusp7 gene,the crawling ability,the integrity of the intestinal was significantly reduced,and the intestinal flora showed a malignant reproductive tendency,suggust that the intestinal function of Drosophila was significantly decreased.In addition,after knock-down the duap7 gene,the antioxidant capacity,anti-starvation ability and heat-stimulation tolerance of Drosophila was significantly reduced compared with control group.By the Western Blot,we found that the ubiquitinated proteins level was abnormally increased and the autophagy-related proteins level was significantly reduced in the dusp7 knock-down Drosophila.The results indicate that the ubiquitin-specific protease d USP7 maintains the normal lifespan of Drosophila by regulating proteostasis.2.After adding 2,5-Dimethyl-celecoxib(DMC),a derivative of celecoxib,into the food of Drosophila while knock-down the dusp7 gene.The lifespan of Drosophila recovered about 6.3%;and partially saved the crawl ability,the anti-stress ability and intestinal function of the Drosophila.The experiment suggust that after using DMC to treat the Drosophila that knock-down dusp7 gene,the level of ubiquitination was decreased,the expression of autophagy-related proteins was significantly enhanced,and autophagy-related genes was enhanced.The results indicate that DMC can partially restore the lifespan of the Drosophila that knock-down dusp7 gene by restoring proteostasis.