IFIH1 Gene

The IFIH1 gene (IFIH1 stands for "Interferon Induced With Helicase C Domain 1") is a protein-coding gene located on chromosome 2q24.2. The IFIH1 gene codes for MDA5 (Melanoma Differentiation-Associated Gene 5), a cytoplasmic sensor for viral nucleic acids (RNA). MDA5 plays an important role in the recognition of viral infections and the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Thus, 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.

MDA5 and viral RNA recognition: The protein MDA5, encoded by the IFIH1 gene, is responsible for the detection of members of the Picornaviridae family (e.g. encephalomyocarditis virus (EMCV)/mengo encephalomyocarditis virus). It recognizes the coronavirus SARS-CoV-2 as well as other viruses such as dengue virus (DENV), West Nile virus (WNV) and reovirus. MDA5 is also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus, and plays an important role in enhancing innate immune signaling by recognizing RNA metabolites produced by ribonuclease L (RNase L) during viral infection. MDA5 may play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in various tumor cell lines.

MDA5 is able to recognize long dsRNA, the genomic RNA of dsRNA viruses, and replicative intermediates of positive and negative sense RNA viruses. MDA5 has also been shown to interact with a number of chemical modifications of RNA. For example, eukaryotic messenger RNA is frequently methylated at the 2'-O position of the first and second nucleotides downstream of the 5' cap. These structures are referred to as cap1 and cap2, respectively. MDA5 is able to recognize the absence of 2'-O methylation, bind to this type of RNA, and elicit an immune response.

MDA5 and malaria: MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infections.

MDA5 and autoimmune diseases: In addition to its protective role in antiviral responses, MDA5 has also been demonstrated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutières syndrome .

Diseases associated with IFIH1 include:

Singleton-Merten syndrome 1

and

Aicardi-Goutières syndrome 7.

Related pathways include DDX58/IFIH1-mediated induction of interferon-alpha/beta and SARS-CoV-2 infection. An important paralog of this gene is RIGI.

Coronaviruses (CoVs), as well as several other virus families, have been shown to be able to bypass the MDA5-dependent interferon response , preventing activation of the innate immune response to infection.

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10. 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.
11. Yamaguchi K et al. (2018) Differential clinical features of patients with clinically amyopathic dermatomyositis who have circulating anti-MDA5 autoantibodies with or without myositis-associated autoantibodies. Respir Med 140:1-5.
12. Yin X et al.(2021) MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells. Cell Rep 34:108628.