The Functions Of PTEN-Long In Type ?interferon Responses And Antiviral Immunity

The innate immunity is the first-line defense for anti-viral or microbial infection.It also collaborates with adaptive immunity to eliminate foreign invasion.At first,pattern recognition receptors(PRRs)including retinoic acid-inducible gene ?(RIG-?)-like receptors(RLRs),Toll-like receptors(TLRs),NOD-like receptors(NLRs)and DNA sensors recognize pathogen associated molecular patterns(PAMPs)which are certain conserved structures in microbes.Different PAMPs are sensed by specific PRRs.RLRs,including RIG-?,MDA5 and LGP2,mainly recognize cellular double-strand RNA or single-strand RNA from viruses.TLRs are located on the surface of cell or endosome.Most of TLRs recruit adaptor MyD88 to activate dowmstream signal to produce proinflammatory cytokines or type-? interferon(IFN).TLR3 and TLR4 recruit TRIF to activate antiviral response.In antiviral responses,all these signaling pathways lead to the activation of IRF3 and/IRF7 and establishment of antiviral status.Phosphatase and tensin homolog deleted on chromosome 10(PTEN)is a well-known tumor suppressor which acts as a dual specificity phosphatase and is frequently mutated in human cancer.PTEN antagonizes the phosphoinositol-3-kinase(PI-3K)via hydrolyzing PIP3 to phosphatidylinositol 4,5-bisphosphate(PIP2),leading to inhibition of the PI-3K/Akt/mTOR pathway and restriction of cell growth,proliferation and survival.Recently,our group found that except for its established role in tumor suppression,PTEN also plays a critical role in the antiviral innate immunity.We demonstrated that the nuclear import of interferon regulatory factor 3(IRF3),a master transcription factor for interferon(IFN)-? production,is controlled by the phosphorylation status at the position Ser97 in the mode of phosphorylation-off and dephosphorylation-on,and PTEN can dephosphorylate at Ser97 of IRF3 and consequently release IRF3 for nuclear import and activationRecently,a translational variant of PTEN with a long N-terminal extension(PTEN-Long)was discovered,which can be secreted into extracellular environment and penetrate into recipient cells where it exerts a phosphatase function in antagonism of PI-3K/Akt signaling and tumorigenesis.In this study,we demonstrated that PTEN-Long can promote type ? interferon responses and antiviral innate immunity during viral infection in phosphatase activity-dependent manner.In comparison with the canonical PTEN,PTEN-Long can also exert its antiviral function when applied in protein form exogenously,which was confirmed in cell culture and mouse infection model.Furthermore,PTEN-Long can enhance responses of both type ? interferon and pro-inflammatory cytokines,suggesting that PTEN-Long may possess additional functions compared with PTEN.Taken together,current finding of the antiviral function of PTEN-Long may open an avenue for using PTEN-Long in antiviral therapy,in particular,in the PTEN-deficient tumor patient.