Cell Res . . . Breakthrough, Wuhan University's zhongbo team found that ubiquitin adjusts the stability of cGAS and promotes cellular antiviral response and autoimmune.

Inature cyclic GMP amp synthase (CGAs) is an important sensor of cytoplasmic DNA, which can mediate innate immune response and autoimmunity.regulating the activity and stability of CGAs provides a potential strategy for the treatment of viral or autoimmune diseases.on May 26, 2020, Zhong Bo team of Wuhan University published a research paper entitled "usp29 maintains the stability of CGAs and promoters cellular anti viral responses and autoimmunity" online on cell research, which reported that ubiquitin specific proteinase 29 (usp29) can de ubiquitinate and stabilize CGAs, and promote cellular antiviral response and autoimmunity.knockout of usp29 can seriously damage the expression of type I interferon (IFN) and proinflammatory cytokines induced by herpes simplex virus-1 (HSV-1) or cytoplasmic DNA.consistently, usp29m / M mice produced reduced type I IFN and pro-inflammatory cytokines after HSV-1 infection, and were allergic to HSV-1 infection. Br / > from the point of view of the mechanism of the interaction between the infected cells and the infected cells.therefore, the findings reveal the key role of usp29 in innate antiviral response to DNA viruses and autoimmune diseases, and provide insights into the regulation of CGAs.the innate immune response to viral infection is triggered by pattern recognition receptors (PRRS), including toll like receptors (TLRs), RIG-I-like receptors and cytoplasmic DNA sensors.however, RNA polymerase III, IFI16 and ddx41 recognize cytoplasmic DNA in a sequence and / or cell type dependent manner. Nucleotide transferase cyclic gmp-amp (cgamp) synthase (CGAs) detects various sequences of DNA in most types of cells and is considered to be the main cytoplasmic DNA sensor.structural and biochemical studies have shown that at least 45 BP of DNA length is required to firmly activate human CGAs (hcgas) in cells, while longer DNA requires a lower concentration.the binding of DNA with CGAs can induce the formation of stable low molecular weight protein DNA complexes or high molecular weight protein DNA ladders, thus activating the enzyme activity of CGAs, which converts GTP and ATP into cgamp.therefore, cgamp and the adaptor binding proteins Mita (also known as sting and Eris) recruit downstream kinases and activate transcription factors such as IRF3 and NF - κ B, which together induce type I interferon (IFN) and proinflammatory cytokines.type I IFN and proinflammatory cytokines are further amplified to express antiviral immune signals by inducing the expression of a series of genes, and the products of these genes jointly trigger the cellular antiviral response.in addition to viral DNA, CGAs sting pathway also recognizes mitochondrial DNA (mtDNA) induced by apoptosis signal, cytoplasmic accumulation of nuclear DNA induced by stress or enzyme, and leakage of nuclear DNA or DNA repair failure of unstable genome.for example, loss of function mutations in DNase's three major repair exonuclease 1 (TREX1), DNase II and RNase H2 result in excessive production of type I interferon and proinflammatory cytokines, and are associated with Aicardi goutieres syndrome (AGS) and systemic lupus erythematosus (SLE).TREX1 - / - or dnaseii - / - mice showed severe systemic inflammation and even fatal autoimmunity, while the deletion of CGAs in TREX1 - / - or dnaseii - / - mice completely rescued the autoimmune phenotype.in view of the importance of CGAs sting pathway in antiviral immunity and autoimmunity, the activity and stability of CGAs must be strictly controlled to induce protective immune response and avoid harmful immunopathology.various post-translational modifications have been reported to control the activity and stability of CGAs.for example, Akt phosphorylates ser305 on human CGAs or ser291 on mouse CGAs.because ubiquitination strictly controls the stability and activity of CGAs, the researchers hypothesized that deubiquitinases (dubs) mediate the de ubiquitination and stability of CGAs and play an important role in CGAs mediated antiviral immunity and autoimmunity. Br / >was identified as co precipitation with usp29.in the absence or presence of HSV-1 infection, usp29 interacts constitutively with CGAs and uncouples with the polyubiquitin chain linked to K48 of CGAs, thus stabilizing CGAs and promoting CGAs mediated cellular antiviral response.consistently, knockout of usp29 resulted in the constitutive degradation of CGAs and eliminated the autoimmune phenotype of TREX1 - / - mice.these findings provide insight into the mechanism of controlling CGAs stability, antiviral immunity and autoimmunity.reference message: