Based on the results presented here and previously published data, we propose a working model to illustrate the role of DHX29 in MDA5-mediated innate immune response to HMW Poly(I:C) treatment and EMCV infection (Fig 7D). During normal physiological conditions, DHX29 is mainly involved in its function in the protein translation. However, DHX29 may switch its function to sense and initiate MDA5-mediated type I IFN signaling after EMCV infection or HMW Poly(I:C) treatment. By contrast, the major function of LGP2 is to regulate both RIG-I and MDA5 mediated innate immune signaling in response to different viral infection. Overall, our findings identify DHX29 as an RNA co-sensor with MDA5 in innate immune response and provide molecular insights into the mechanisms by which DHX29 controls EMCV-specific and MDA5-mediated antiviral immunity.