The Mechanisms Of Tyrosine Phosphatase PTPN1 And PTPN2 Regulating Antiviral Innate Immune Response

In vertebrates,innate and adaptive immunity are used to protect the host from infections.The innate immune system utilizes a limited number of pattern-recognition receptors(PRRs)to recognize pathogen-associated molecular patterns(PAMPs)of pathogenic microbes.As a member of PAMPs,the virus-derived nucleic acid plays a central role in the initiation of antiviral immunity.Nucleic acid sensing by PRR results in the induction of type I interferons(IFNs)and pro-inflammatory cytokines,which inhibits viral replication and activates adaptive immune responses.It is now well established that the viral RNA,which is abundant in endosome and cytoplasm during virus infection,is sensed by the endosomal Toll-like receptor 3(TLR3)and the cytosolic RNA receptors RIG-I and MDA5.Although there are several DNA sensors have been identified,the cyclic GMP-AMP synthase(cGAS)has been recently defined as a general one.Upon binding of DNA,cGAS catalyzes the synthesis of 2'3' cyclic GMP-AMP(cGAMP),which subsequently binds to the endoplasmic reticulum(ER)associated membrane protein MITA/STING.Activated MITA is then translocated from the ER to the ER-Golgi intermediate compartment(ERGIC)and recruits the kinase TBK1 and the transcription factor IRF3 to facilitate IRF3 phosphorylation by TBK1.The phosphorylated IRF3 dimerizes and then enters the nucleus,where it functions together with other transcription factors to induce the expression of interferons and inflammatory cytokines.Subsequently,MITA is transported via the Golgi apparatus to the perinuclear punctate structures where it undergoes degradation.Although proper activation of cGAS-MITA is essential for initiating host defense to pathogen invasion,sustained immune signaling responses to foreign or self-DNA might lead to autoimmune diseases.MITA is regulated by various posttranslational modifications,such as phosphorylation,poly-ubiquitination and sumoylation.Recently,the Takeda G protein coupled receptor-5(TGR5)was reported to be a positive regulator in innate antiviral response.Viral infection induced the recruitment of the tyrosine kinase SRC to TGR5,which then facilitates the tyrosine phosphorylation and subsequent activation of MITA.However,the function and mechanism of tyrosine phosphorylation of MITA need further investigation.In this study,we identified non-receptor tyrosine phosphatase PTPN1 as an interacting protein of MITA by affinity enrichment and mass spectrometry.Subsequent studies have shown that PTPN1,together with its homologous molecule PTPN2,negatively regulates the expression of type I interferon induced by DNA viruses.The deletion of PTPN1 and PTPN2 can significantly enhance the antiviral response of cells.Further studies showed that PTPN1 and PTPN2 can catalyze the dephosphorylation of MITA at tyr245.On the one hand,the dephosphorylation of MITA can inhibit its dimerization;on the other hand,it can promote the degradation of MITA through the 20 S proteasomal pathway and attenuate innate antiviral response.