RIG-I-like receptors, Toll-like receptors (TLRs), Nod-like receptors, and DNA sensors are germline-encoded pattern-recognition receptors (PRRs) that serve as the first line of defense against invading pathogens, including bacteria and viruses [1, 2]. PRRs possess the abilities to recognize pathogen-associated molecular patterns (PAMPS) and subsequent to the detection of PAMPs, PRRs trigger the activation of common type I interferon (IFN), NF-κB, inflammasome, and autophagy signaling pathways [1–5]. The consequent activation of these pathways induces the expression of cytokines and chemokines that facilitate the host pathogen defense and thus initiate the adaptive immune response. Among the PRRs, two RNA helicases such as Retinoic acid-inducible gene 1 (RIG-I, DDX58) and melanoma differentiation-associated protein 5 (MDA5), belonging to RIG-I-like receptor family, are considered to be the most important cytosolic viral RNA sensors . Although both RIG-I and MDA5 can respond to West Nile virus and dengue virus , they also recognize specific sets of viruses . While MDA5 primarily senses positive-strand viruses from the Picornaviridae family, such as Encephalomyocarditis virus (EMCV), RIG-I recognizes RNA viruses, including Sendai virus (SeV), vesicular stomatitis virus (VSV), and influenza virus [7, 9, 10]. Further studies and structural analysis of RIG-I and MDA5 showed that RIG-I recognizes the 5´-triphosphate group (5´-ppp) and blunt end of short (low molecular weight) RNAs with high affinity [11–14]. In contrast, MDA5 recognizes the internal duplex structure of long (high molecular weight) double strand (ds)RNAs with a weaker affinity [1, 15], thus resulting in the aggregation of MDA5 and its interaction with MAVS (VISA, IPS-1, Cardif) to trigger downstream type I IFN signaling cascade [16–19]. Of note, previous observation demonstrates that higher-order structure RNA comprising of both dsRNA and single strand RNA from EMCV-infected cells contain MDA5-stimulating activity , suggesting that other protein factors are involved in the selection and recognition of EMCV viral RNA. To this end, such potential candidate may be LGP2 (Laboratory of Genetics and Physiology 2), a cytoplasmic DExH helicase that shares the domain structure of RIG-I and MDA-5 with the exception of the CARD domains . Paradoxically, LGP2 has been reported to exert both positive and negative effects on RIG-I and MDA5 regulation in different cell types in response to different viruses [15, 21–24], thus questioning its’ specificity to MDA5-mediated viral RNA selection and recognition. Based on these premises, the identification of protein factors that are involved in the selection and recognition of MDA5 for viral RNA is warranted.