MDA5 and LGP2: Accomplices and Antagonists of Antiviral Signal Transduction

Abstract

Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral transcriptional response that provides an initial barrier to replication and impacts both innate and adaptive immune responses. Retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) proteins mediate intracellular virus recognition and are activated by viral RNA ligands to induce antiviral signal transduction. While the mechanisms of RIG-I regulation are already well understood, less is known about the more enigmatic melanoma differentiation-associated 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2). Emerging evidence suggests that these two RLRs are intimately associated as both accomplices and antagonists of antiviral signal transduction.C ellular antiviral signaling is initiated following recognition of virus-encoded molecular signatures, often in the form of nucleic acids. Infection by RNA viruses results in cytosolic accumulation of double-stranded RNA (dsRNA) or otherwise chemically distinct, non-self RNA species. Sentry proteins in the cytoplasm recognize characteristics of non-self RNAs and can trigger downstream signal transduction pathways that culminate in activated antiviral transcription regulators (1-3). These factors accumulate in the nucleus, where they drive the expression of virus-induced genes, including the primary antiviral cytokine, beta interferon (IFN-␤), and diverse direct and indirect antiviral effectors (4).One group of intracellular responders, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), includes the proteins RIG-I (5), melanoma differentiation-associated 5 (MDA5) (6), and laboratory of genetics and physiology 2 (LGP2) (7). Similar in structure and function, these proteins share significant sequence homologies that define them as the products of an evolutionarily conserved gene family (8) (Fig. 1A). The RLR proteins are thought to share the ability to detect molecular signatures of virus infection and activate antiviral signaling cascades, but they differ in both their RNA recognition capacities and signaling properties (9, 10). RIG-I, MDA5, and LGP2 share homologous DECH box helicase domain regions that have intrinsic dsRNA binding and ATP hydrolysis functions and a C-terminal domain that has been implicated in binding to RNA termini and autoregulation (11-13). RIG-I and MDA5 both have tandem N-terminal caspase activation and recruitment domain (CARD) motifs, protein interaction domains that mediate associations with upstream and downstream regulatory machinery. The CARDs are regulated by posttranslational modifications, including ubiquitination and phosphorylation (14-16). Current evidence indicates that RNA recognition by RIG-I and MDA5 is accompanied by CARD dephosphorylation, enabling their productive interaction with signaling machinery. Much of the knowledge of the RLR signaling pathway was developed by detailed study of RIG-I, the prototype RLR (17), and investigations of MDA5 have contributed greatly to a general paradigm for RLR signaling (Fig. 1...

Loss of RIG-I leads to a functional replacement with MDA5 in the Chinese tree shrew

“…Besides MDA5, LGP2 acts as a regulator of RLR-mediated antiviral signaling and was reported to play apparently conflicting roles in different studies (10,41). In contrast to negative regulation in the RIG-I-mediated signaling pathway (4,42,43), tree shrew cells lacking tLGP2 exhibited a decreased IFNB1 mRNA expression in response to RNA virus infections (Fig.…”

Antiviral RNA recognition and assembly by RLR family innate immune sensors

“…However, this EMCV-encoded MDA5 agonist RNA was identified based on its association with LGP2, and binds poorly to MDA5. Therefore, while RNA features specific for MDA5 recognition were not revealed, this study added to the increasing evidence that LGP2 acts as a collaborator for MDA5 RNA recognition [47]. Further attempts to isolate MDA5-specific RNA ligands have exploited photo-activated RNA crosslinking of measles virus-infected cells to preserve low-affinity interactions during subsequent immunoprecipitation.…”

Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway

“…IRF3 is a transcription factor essential for host defense and is rapidly activated upon virus infection to drive the antiviral response, which includes many genes. Within PRR pathways, many factors converge on IRF3, including the TBK1 and IKKε protein kinases, the MAVS adaptor protein, and activation cofactors like CBP/ p300 (9). Because signaling by KIN1400 is dependent on MAVS and IRF3, our results suggest that the KIN1400 compounds likely target factors at or above the level of MAVS in the RLR signaling pathway to drive IRF3 activation.…”

“…Cellular proteins known as pathogen recognition receptors (PRRs), including the RIG-I-like receptors (RLRs) and Toll-like receptors, function to detect viral RNA and signal an innate immune response essential for limiting and controlling viral infections in the host (8)(9)(10)(11)(12). Upon recognition and engagement of viral pathogen-associated molecular patterns (PAMPs), including viral nucleic acid and other macromolecules, PRRs signal downstream to activate transcription factors, including interferon (IFN) regulatory factor 3 (IRF3), NF-B, and others, which in turn induce the expression of many innate immune and antiviral genes and the production of antiviral gene products, proinflammatory cytokines, chemokines, and IFNs.…”