Molecular Mechanisms Of 2A-DUB Regulating CGAS-STING Signaling Pathway

The natural immune system includes complex signaling networks,which are composed of immune cells,pattern recognition receptors,signaling proteins,and cytokines.STING is a key signaling protein in natural immune signaling pathways that recognize DNA pathogen associated molecular patterns.Disturbance of STING can lead to excessive production of inflammatory mediators,which can lead to inflammation and autoimmune diseases.Therefore,it is very important to strictly regulate STING so that it exerts normal immune effects to maintain the steady state of the internal environment.This article studied the mechanism of 2A-DUB interacting with STING to down-regulate the c GAS-STING pathway,aiming at finding possible targets for drug research to treat autoimmune diseases.Firstly,We found that the expression of2A-DUB gene is activated by DNA viruses or DNA stimulants,and the protein2A-DUB can negatively regulate antiviral responses and inflammatory responses.Then we studied the regulatory effect of 2A-DUB on the c GAS-STING pathway.We found that 2A-DUB can negatively regulate the c GAS-STING pathway.The interaction between some key signaling proteins of this pathway and 2A-DUB was explored by the co-immunoprecipitation.We found that 2A-DUB interacted with STING significantly.So we targeted STING and conducted a more in-depth study on the mechanism of the interaction between 2A-DUB and STING.We analyzed the interaction between STING and 2A-DUB domain deletion mutants to determine the domain required for the 2A-DUB-STING interaction.Research revealed that the SWIRW domain is an indispensable domain for the interaction between 2A-DUB and STING.Next,we evaluated the role of 2A-DUB deubiquitinase activity in negatively regulating the c GAS-STING pathway.We found that 2A-DUB can deubiquitinate STING.The experiment of deubiquitinating STING by the domain deletion mutant of2A-DUB proved that the MPN and SWIRM domains of 2A-DUB are the key domains to deubiquitinate STING.Our research shows that 2A-DUB interacts with STING through the MPN domain and SWIRM domain to deubiquitinate STING and thereby down-regulate the c GAS-STING pathway.Therefore,2A-DUB is a key repressor of innate immunity and it can be used as a potential therapy for inflammatory and autoimmune diseases.