MDA5

MDA5 stands for: Melanoma Differentiation-Associated Protein 5. MDA5 is encoded by the IFIH1 gene, which is located on chromosome 2q24.2. MDA5 is an intracellular sensor for viral RNA that triggers the innate immune response. MDA5 recognizes the length and secondary structure of RNA and binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, resulting in a proinflammatory response that involves interferons. Coronaviruses (CoVs), as well as several other virus families, have been shown to be able to evade the MDA5-dependent interferon response, preventing activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing the function of natural killer cells in malaria infections. In addition to its protective role in antiviral responses, MDA5 has also been shown to be involved in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus and Aicardi-Goutieres syndrome.

MDA5 thus plays an important role in the recognition of viral infections and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines (Wu XM et al. 2020). Its ligands include mRNA lacking 2'-O-methylation at its 5' cap and long dsRNA (>1 kb in length) (Peisley A et al. 2011). After ligand binding, it associates with the mitochondrial antiviral signaling protein (MAVS/IPS1), which activates IKK-related kinases: TBK1 and IKBKE, which phosphorylate interferon regulatory factors: IRF3 and IRF7, which in turn activate the transcription of antiviral immunological genes, including the interferons (IFNs) IFN-alpha and IFN-beta.

MDA5 is responsible for the detection of members of the Picornaviridae family such as encephalomyocarditis virus (EMCV), mengoencephalomyocarditis virus (ENMG) and rhinovirus (Lamborn IT et al. 2017).

MDA5 recognizes the coronavirus SARS-CoV-2 (Yin X et al.2021). MDA5 recognizes the length and secondary structure of RNA and binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, leading to a proinflammatory response that includes interferons. Coronaviruses (CoVs), as well as several other virus families, have been shown to be able to evade the MDA5-dependent interferon response, preventing activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing the function of natural killer cells in malaria infections. In addition to its protective role in antiviral responses

MDA5 can also recognize other viruses such as dengue virus (DENV), West Nile virus (WNV) and reovirus. It is also involved in antiviral signaling in response to viruses that contain a dsDNA genome, such as vaccinia virus. MDA5 plays an important role in enhancing innate immune signaling by recognizing RNA metabolites produced by ribonuclease L (RNase L) during viral infection. May play an important role in enhancing the function of natural killer cells and may be involved in growth inhibition and apoptosis in various tumor cell lines.

1. Lamborn IT et al. (2017) Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. J Exp Med 214:1949-1972.
2. Peisley A et al. (2011) Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc Natl Acad Sci U S A 108:21010-21015
3. Wu XM et al. (2020) NOD1 Promotes Antiviral Signaling by Binding Viral RNA and Regulating the Interaction of MDA5 and MAVS. J Immunol 204:2216-2231.
4. Yin X et al.(2021) MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells. Cell Rep 34:108628.