hnRNPA2B1 recognizes RNA virus SFTSV infection through mitochondrial DNA

The heterogeneous nuclear ribonucleoprotein (hnRNPA2B1, hereafter A2B1) was identified as a novel nuclear DNA sensor that mediates antiviral immunity by recognizing viral DNA in the nucleus. However, it remains largely unclear whether A2B1 could function as a nucleic acid pattern-recognition receptor during cytoplasmic RNA virus infection. Severe fever with thrombocytopenia syndrome virus (SFTSV), which causes severe hemorrhagic fever, is a tick-borne RNA virus that poses a serious threat to public health. In this study, we observed that during SFTSV infection, the interaction between A2B1 and SFTSV nucleoprotein (NP) promoted the retention of A2B1 in the cytoplasm. Importantly, the transcription levels of IFNβ and inflammatory cytokines were decreased with A2B1 silenced, similar to the expression levels of p-TBK1 and p-IRF3. We observed that cytoplasmic A2B1 was involved in recognizing mislocated mitochondrial DNA (mtDNA) and triggered the STING-TBK1 axis to potentiate antiviral type I interferon responses. Thus, A2B1 could be identified as a novel cytoplasmic DNA sensor and sense RNA virus SFTSV infection by monitoring mislocalized mtDNA, stimulating antiviral immune response. Our study may provide new insights into host defense against RNA virus infections and should be important for clarifying the complex interaction between A2B1 and virus infection.IMPORTANCEhnRNPA2B1 (hereafter A2B1) has been identified as a novel DNA sensor for surveillance of infection from DNA viruses. SFTSV is an RNA virus that causes SFTS with a high case-fatality rate of up to 45.7%. Although SFTSV could utilize A2B1 in viral RNA synthesis for proliferation, whether SFTSV can be recognized by DNA sensor A2B1 and initiate innate immune response remains unexplored. Our study illustrates a complex interplay where SFTSV nucleoprotein (NP) seizes the newly synthesized A2B1 in the cytoplasm, which senses leaked mitochondrial DNA, leading to the activation of the STING-TBK1 signaling pathway to promote IFNβ production. These findings reveal the role of nuclear DNA sensor A2B1 in sensing RNA virus SFTSV infection in the cytoplasm and expand the new understanding of A2B1 in innate immunity. By targeting the A2B1-STING axis, we can potentially develop novel antiviral therapies against SFTSV and possibly other RNA viral infections.