Cell Research . . . The bell wave group found a new mechanism for antiviral immunity and autoimmune regulation.

In the process of virus infection and replication, a large number of viral nucleic acids (such as DNA, RNA or RNA-DNA complexes) are produced in the cytoplasm of the plant.the cytoplasmic DNA receptor CGAs recognizes viral DNA or RNA-DNA complex, and synthesizes 2 '- 3' - cgamp from ATP and GTP. Cgamp, as the second messenger, binds to the adaptor protein sting / Mita to promote its oligomerization, activate a series of signal cascade reactions, and induce the expression of downstream genes such as interferon type I to produce antiviral immune response.in addition, mutations in host encoded DNA enzymes such as TREX1 or DNase II, or the release of nuclear DNA into the cytoplasm and accumulation in the cytoplasm during tumor radiotherapy or chemotherapy can activate the CGAs sting signaling pathway, leading to severe inflammatory reactions.therefore, it is important to understand the mechanism of CGAs activation and homeostasis in order to understand the antiviral immune response and inflammatory response.on May 26, 2020, Professor Zhong Bo of Wuhan University published a research paper entitled "usp29 maintains the stability of CGAs and promoters cellular anti responses and autoimmunity" online in the journal Cell Research.the team found that usp29 interacts with CGAs continuously to remove ubiquitination modification of K48 link on CGAs and inhibit its degradation through proteasome pathway, thus promoting antiviral immune response and autoimmunity induced by TREX1 knockout.the team first found that actinomycin treatment led to rapid degradation of CGAs in THP-1 cells, while MG132 treatment completely inhibited this process and promoted the accumulation of CGAs and ubiquitination in cells, indicating that CGAs is regulated by real-time and dynamic ubiquitination and de ubiquitination modification under resting state.subsequently, the team screened the de ubiquitinase that interacted with CGAs, and found that usp29 interacted with CGAs continuously.knockdown of usp29 in human cell lines or primary mouse cells significantly inhibited the activation of IRF3 and NF KB induced by HSV-1 infection or cytoplasmic DNA transfection, inhibited the expression of cytokines such as interferon I and promoted the replication of HSV-1.compared with wild-type mice, usp29 deficient mice were more susceptible to lethal HSV-1 infection, had earlier death time, higher mortality, and significantly lower levels of cytokines such as interferon in peripheral blood.further studies showed that usp29 removed the ubiquitin chain of k271 K48 linkage type on CGAs, prevented CGAs from degradation through proteasome pathway, and maintained CGAs protein level.in usp29 knockout mouse primary cells or organs, the protein level of CGAs was significantly decreased, the half-life of CGAs was shortened, and the cgamp level after DNA transfection was significantly reduced.in usp29 knockout cells, CGAs supplementation can completely restore the expression of downstream genes induced by HSV-1 infection, promote the production of cgamp after DNA transfection, and inhibit the replication of HSV-1.interestingly, knockdown of usp29 in human cell line THP-1 or knockout of usp29 in mouse cells or organs did not affect the expression level of CGAs mRNA, suggesting that usp29 regulates the antiviral immune response by regulating the homeostasis of CGAs protein level.finally, the team studied the regulatory function of usp29 on inflammation and autoimmunity induced by TREX1 knockout.specifically, the team prepared TREX1 - / - mice and obtained TREX1 / usp29 double knockout mice. It was found that usp29 knockout can save the lethal autoimmune phenotype caused by TREX1 deficiency, inhibit the differentiation of GCB cells in spleen, activation of T cells, infiltration of immune cells in lung and heart, and expression of inflammatory cytokines and total IgG in peripheral blood.these results suggest that usp29 promotes inflammatory response and autoimmunity by regulating CGAs protein levels, suggesting that usp29 may be a potential target for the treatment of some autoimmune diseases. it is reported that Zhang Qiang, a doctoral student of Zhongbo laboratory, is the first author of the paper. this paper is also the third time that the research results of Professor Zhong Bo's research group have been published in cell research journal in recent three years (the previous two cell research papers: Liuyu T, Yu K, ye L, Zhang Z, Zhang m, Ren y, Cai Z, Zhu Q, Lin D, Zhong b *, Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS. Cell Res, 2019, 29(1):67-79.；Zhang M#, Zhang MX#, Zhang Q, Zhu GF, Yuan L, Zhang DE, Zhu QY, Yao J, Shu HB, Zhong B*. USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA. Cell Res. 2016, 26(12): 1302-1319.）。 original link: plate maker: Qi sauce