RIG-I and MDA5 are key RNA sensors that recognize different sets of viruses. MDA5 primarily senses positive-strand viruses from the Picornaviridae family, such as EMCV, whereas RIG-I recognizes SeV, VSV, and influenza virus [7, 9, 10]. Although it is not clear how RIG-I and MDA5 specifically respond to different viruses, it is likely that differences in viral RNA ligand specificity (5´ ppp end of short RNA for RIG-I vs. internal duplex structure of long dsRNA for MDA5) and RNA binding affinity (high affinity for RIG-I vs. low affinity for MDA5) may contribute to the distinct viral recognition of MDA5 and RIG-I in the innate immune response. Recently, several RNA helicases have been implicated in viral immunity and protein translation . For example, DDX1, DDX3, DDX5, DDX6, DDX24, DDX56, DDX60, DHX9, and DHX30 are implicated with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, herpes simplex virus, VSV replication and innate immune response [26, 49, 50]. In particular, DDX1, DDX21, and DHX36 form a complex with adapter protein, TIR-domain-containing adapter-inducing interferon-β (TRIF) to recognize dsRNA from influenza virus and reovirus . DDX41 can recognize intracellular DNA and activate STING-mediated type I IFN signaling . However, potential RNA helicase(s) involved in the recognition of EMCV remain to be identified. In this study, we have provided compelling evidence that the RNA helicase DHX29 functions as an RNA co-sensor along with MDA5, and plays a critical role in innate immune signaling and immunity in response to HMW Poly(I:C) treatment and EMCV infection, but definitely not to LMW Poly(I:C) treatment or VSV infection. However, in contrary to our observation, a previous study reported that DHX29 is expressed solely in lung airway cells, but not in human PBMCs (such as B cells and T cells), primary monocytes, THP-1 cells and 293T cells, and thus does not play a role in type I IFN signaling in immune cells . Moreover, previous study suggested that DHX29 interacts with RIG-I and functions as a co-receptor for sensing poly I:C, poly dAdT:dAdT and VSV infection . However, the interaction between DHX29 and MDA5 was never explored in their study .