Function And Molecular Mechanisms Of USP25-mediated Regulation Of Colon Infections And Inflammations And Colon Cancer

IBD is a chronic remitting and relapsing inflammatory disorder of the gastrointestinal(GI)tract characterized by abdominal pain,diarrhea and bloody stools and comprises two primary diseases: Crohn’s disease and ulcerative colitis(UC).Genome-wide association study(GWAS)and gut microbiome analyses have implicated imbalance of protective and aggressive resident bacteria in IBD patients,but the exact causal mechanisms underlying IBD are not fully understood.CRC is a result of interactions between genetic and environmental factors,including chronic inflammation,somatic mutation,nutrition,and gut microbiota.Chronic inflammation is one of the important factors leading to CRC,so understanding the molecular mechanism of the occurrence and development of CRC is very important for the early diagnosis and the prognosis of patients with CRC.We have found that USP25 regulates signal transduction mediated by PPRs such as TLRs,RLRs and cytoplasmic DNA sensors and host antiviral immune response by deubiquitating and stabilizing the TRAF3.Studies have shown that PPRs mediated signal transductions play a key role in regulating intestinal infections,inflammatory response and tumorigenesis.We speculate that USP25 may be involved in intestinal infection and inflammation and even tumorigenesis by regulating the above signaling pathways.In this study,we found that USP25 knockout mice were more resistant to experimental colitis,intestinal bacterial infection and colon cancer,and USP25 deficiency resulted in hyper-immune responses after dextran sulfate sodium(DSS)treatment or Citrobacter rodentium(CR)or Salmonella enterica Typhimurium(ST)infection and higher expression of cytokines or antimicrobial peptides in peripheral blood and colon tissues than wild-type mice.To molecular mechanisms,we demonstrated that USP25 inhibited the immune response to intestinal anti-bacterial infection by obstructing the transduction of toll like receptor(TLR)signaling pathways,and then promoted intestinal inflammation and bacterial infection;in addition,in multiple mouse models of intestinal tumors USP25 promoted intestinal tumorigenesis by up-regulating the expression of Wnt related genes,such as Lgr5,Sox9 in Wnt-β-catenin signaling pathways,inhibiting the level of SOCS3 and promoting the activation of STAT3.Further,we found that gavage-injected AZ1,the small molecular inhibitor of USP25,potentiated immune responses after induction of experimental colitis or intestinal bacterial infections in mice that promoted clearance of infected bacteria and resolution of inflammation,and attenuated colonic tumorigenesis.Linking clinical data,we found that the USP25 levels were positively or negatively correlated with Fusobacterium nucleatum colonization and β-Catenin levels or SOCS3 levels in human colorectal tumor biopsies,respectively,and predicted poor prognosis of patients with cancers in the gastrointestinal system.Our findings suggested that USP25 plays an important regulatory role in the development of colitis,intestinal bacterial infection and colorectal cancer in mice and USP25 can serve as a promoter and druggable target for gastrointestinal infections and cancers,and provided new strategies for the diagnosis and treatment of intestinal diseases.