The Role And Mechanism Study Of USP39 In Type Ⅰ Interferon Antiviral Response

Multiple signaling cascades are involved in antiviral immune responses.Viral infection initiates a series of signaling pathways,which activate the transcription of interferon regulatory factor 3(IRF3)and nuclear factor-κB(NF-κB),subsequently inducing the production of type Ⅰ interferon and proinflammatory cytokines.Protein modifications include methylation,acetylation,phosphorylation,SUMOylation and ubiquitination,which play important roles in the antiviral process.The mechanisms of ubiquitination and deubiquitination regulating this process are not fully understood,which become increasingly attractive.IFNs induce a series of cascades including the activation of the Janus kinase(JAK)and signal transducers and activators of transcription(STAT)to exert their antiviral function.STAT1 participates in the regulation of all three classes of IFNs signaling.Activated STAT1,STAT2 and IRF9 form a complex,which translocates into the nucleus and binds to the IFN-stimulated response element(ISRE)to induce the expression of interferon stimulated genes(ISGs).STAT1 is generally activated by phosphorylation at 701 tyrosine site.Sufficient p Y701-STAT1 level in the nucleus is critical to sustain interferon signaling and antiviral responses.In order to systematically explore the role of deubiquitinases in antiviral immunity,we screened a si RNA library which includes almost all of the deubiquitinases using RNA virus vesicular stomatitis virus(VSV).In the study,we found that USP39,which had not been reported,showed a robust antiviral effect against VSV infection.Further results demonstrated that USP39 did not affect the production of type Ⅰ IFN,but positively promoted JAK/STAT signaling by inhibiting degradation of ubiquitinated STAT1,and resulted in enhanced ISRE promoter activity and the expression of ISGs.Our results also showed that USP39 interacted with HNRNPC and KPNA1,which may affect p Y701-STAT1 nuclear import.However,the specific mechanism remains to be elucidated.Taken together,we screened and identified that USP39 acted as a positive regulator of type Ⅰ IFN signaling.USP39 did not affect the production of type Ⅰ IFN,but stabilized STAT1 and enhanced the transcription of downstream ISGs.Our results may provide a new target for IFNs antiviral therapeutic treatments.