| Pattern-recognition receptors(PRRs)are able to detect pathogen-associated molecular patterns(PAMPs),including RNA,DNA,RNA-DNA hybrid produced by virus during its infection and replication.Upon recognizing PAMPs,PRRs change their conformations,then recruit adaptor proteins or catalyze second messenger molecules to activate adaptor proteins,induce a series of signaling cascades and eventually induce expression of an array of downstream genes to elicit antiviral immune responses.Studies demonstrated that cGAS binds viral DNA upon detection of it,leading to the synthesis of cGAMP,which binds to MITA and activates it.Activated MITA then to trigger the downstream antiviral signaling response,resulting in the production of type I interferon and proinflammatory cytokines.Moreover,MITA-knockout mice exhibit more sensitive to HSV-1,phosphorylation of IRF3 and downstream gene expressions almost restricted in MITA-knockout mice cells after infection of HSV-1 or transfection of cytoplasmic-DNA.Taken together,these studies uncovered that MITA is a key protein to induce DNA signaling transduction and plays a key role in antiviral innate immune responses.Various post-translational modifications have been reported to regulate the activity of MITA,including ubiquitination and deubiquitination.Lots of studies have demonstrated the the function of E3 ligases and their mechanism of ubiquitinating MITA.However,the function and mechanism about deubiquitination of MITA is not fully understood.To get more information about how DUBs affect the MITA-mediated signaling responses.We did a screening between MITA and DUBs,found that USP49 interacts with MITA,and their interaction is induced by infection of HSV-1 or transfction of dsDNA and cGAMP.Afterwards,we found that knockout or knockdown of USP49 in THP-1 potentiated HSV-1-induced production of type I interferons and proinflammatory cytokines and promote the MITA-mediated signaling responses.Furthermore,we established the Usp49 knockout mice and found Usp49 knockout mice potentiate HSV-1-,dsDNA-,cGAMP-induced production of type I interferons and proinflammatory cytokines and impair HSV-1 replication significantly.Consistently,Usp49 knockout mice exhibit resistance to lethal HSV-1 infection and attenuated HSV-1 replication compared to wild-type mice.Mechanistically,USP49 removes K63-linked ubiquitin chains from MITA after HSV-1 infection which inhibits the aggregation of MITA and the subsequent recruitment of TBK1 to the signaling complex.These findings suggest a critical role of USP49 in terminating innate antiviral responses and provide insights into the complex regulatory mechanisms of MITA activation. |
