The Zhongbo team at Wuhan University found an important function and mechanism for ubiquitinase to regulate the immune and tumor occurrence of intestinal infections.

Pattern recognition receptors (PPRs) are widely expressed in various types of intestinal epithelial cells. They recognize the invading pathogenic microorganisms and initiate a series of signal cascade reactions, thus inhibiting the replication of pathogenic microorganisms, clearing the infected cells and repairing the damaged intestinal epithelium.previous research results of Zhong Bo team show that USP25 can promote antiviral innate immunity by regulating toll like receptor (TLR) or RIG-I-like receptor (RLR) signaling pathway, and inhibit TLR mediated inflammatory response.PRR mediated signaling pathway plays an important role in intestinal infection immunity.on July 6, 2020, the research team of Professor Zhong Bo, School of medical research / School of life sciences, Wuhan University, and center for frontier science of immunology and metabolism published an online research paper entitled "the deubiquitinase USP25 supports colonial inflammation and bacterial infection and promoters chromatic cancer" in the journal Nature cancer.this study reported the important functions and mechanisms of ubiquitinase USP25 in regulating intestinal inflammation, infection and tumorigenesis, providing a new target for the treatment of intestinal diseases.this is another major breakthrough in the field of deubiquitinase regulating inflammation and tumorigenesis.the team first found that USP25 was widely expressed in digestive tract tissues, colon epithelial cells and lamina propria monocytes, small intestine and colon crypt cells. Moreover, the number of Paneth cells in small intestinal crypt and goblet cells in intestinal villi of USP25 knockout mice increased, while the number of proliferating cells and stem cells in crypt decreased, suggesting that USP25 regulates the differentiation and proliferation of intestinal cells.the results of DSS colitis and bone marrow transplantation experiments showed that USP25 knockout in non bone marrow-derived cells mediates the resistance to DSS colitis, and this process depends on the regulation of USP25 on intestinal symbiosis rather than type I interferon signaling pathway.in the model of Citrobacter ratus or Salmonella typhimurium infection, the expression levels of inflammatory cytokines and antimicrobial peptides in serum and intestinal tissue of USP25 knockout mice were significantly increased, resulting in stronger immune response and better inhibition of the replication of intestinal infection bacteria.in the colon cancer model of apcmin / + mice infected with Fusobacterium nucleatum, USP25 knockout significantly inhibited the occurrence of colon tumors and the colonization of Fusobacterium nucleatum in colon tumors.further studies showed that the expression level of USP25 was positively correlated with the colonization of Fusobacterium nucleatum.the expression level of USP25 in colon tissue or colon epithelial cells induced by bacterial infection and DSS was significantly increased, which indicated that intestinal infection inhibited host anti infection immune response by up regulating the expression of USP25. Br / > and the development of intestinal cancer in mice with ap-53m / > were studied.the results showed that the expression level of USP25 was increased in the above three intestinal tumor models, and USP25 knockout significantly reduced the number of intestinal tumors, reduced the incidence of tumor and improved the survival time of mice.interestingly, in the above three tumor models, USP25 knockout did not affect the expression of inflammatory cytokines in tumor tissues, indicating that USP25 mainly regulates the expression of related cytokines during acute intestinal infection.the results of transcriptome sequencing of DSS colitis tissue and the study of intestinal organs showed that USP25 knockout promoted the expression of SOCS3, but inhibited the expression of Wnt signaling pathway related genes.the results of immunohistochemistry and Western blotting showed that the level of SOCS3 was increased in USP25 knockout mice, while the levels of PSTAT3 and Sox9 downstream of Wnt signaling pathway were decreased.in human colon cancer tissues, USP25 level was negatively correlated with SOCS3, but positively correlated with PSTAT3 and β - Catenin, indicating that USP25 promotes the progress of intestinal tumor in mice by regulating Wnt signaling pathway and socs3-pstat3 axis.finally, the team studied whether targeted USP25 could be used to treat intestinal infection, inflammation and tumorigenesis.firstly, the team synthesized az1, an inhibitor of USP25 / USP28, and found that az1 inhibited Wnt signaling pathway and promoted the expression of downstream inflammatory cytokines induced by Citrobacter infection in wild-type colon like organs, but not in USP25 knockout organs, indicating that az1 selectively regulates USP25 in related pathways.secondly, az1 did not affect bacterial replication in vitro. After intragastric administration of az1, the growth, spleen and lymph nodes of mice did not significantly expand or shrink, nor did the composition of intestinal flora in mice change significantly, indicating that az1 did not directly regulate the growth of bacteria.finally, by intragastric administration of az1, it can inhibit DSS induced colitis, inhibit the infection of Citrobacter in mice, and the occurrence of intestinal tumors in AOM / DSS and AOM / VIL CRE; trp53fl / FL mice, indicating that targeted USP25 can be used as a drug target for the treatment of inflammation and tumor development related to intestinal infection in mice.this study provides a theoretical basis and molecular target for the treatment of intestinal diseases with targeted de ubiquitinase.Wang Xiaomeng, PhD student of Zhongbo laboratory, is the first author of this paper.Professor Dong Chen of Tsinghua University, Professor Fang Jingyuan of Renji Hospital of Shanghai Jiaotong University, Professor Xiong bin of Central South Hospital of Wuhan University and Lin Dandan, deputy chief physician of Renji Hospital of Wuhan University, have also made important contributions to this paper.article link: the official account is hosted by the microbiology resource center and the big data center of the Institute of Microbiology, Chinese Academy of Sciences. 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