A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation

Abstract

Induction of interferons during viral infection is mediated by cellular proteins that recognise viral nucleic acids. MDA5 is one such sensor of virus presence and is activated by RNA. MDA5 is required for immunity against several classes of viruses, including picornaviruses. Recent work showed that mutations in the IFIH1 gene, encoding MDA5, lead to interferon-driven autoinflammatory diseases. Together with observations made in cancer cells, this suggests that MDA5 detects cellular RNAs in addition to viral RNAs. It is therefore important to understand the properties of the RNAs which activate MDA5. New data indicate that RNA length and secondary structure are features sensed by MDA5. We review these developments and discuss how MDA5 strikes a balance between antiviral immunity and autoinflammation.

Keywords: IFIH1; MDA5; RNA; antiviral defence; autoinflammation; type I interferon.

Figure 1

Overview of the MDA5 Pathway. MDA5 comprises two N terminal CARD domains, a central helicase domain, and a C terminal domain (CTD). Both the helicase domain and the CTD are involved in RNA binding. MDA5 recognises synthetic RNAs, such as poly I:C, viral RNAs, and endogenous RNAs. Length and secondary structure are likely to be key determinants of MDA5 activation, which has been suggested to be mediated by multimerisation of the protein on RNA agonists. This results in the clustering of multiple CARD domains, which, in turn, allows the engagement of MAVS. Activation of this adaptor protein triggers a signalling cascade involving TBK1 and IRF3, leading to transcriptional induction of the genes encoding type I IFNs and other antiviral genes. CARD, caspase activation and recruitment domain; MAVS, mitochondrial antiviral signalling protein.