IFIH1

Interferon-induced helicase C domain-containing protein 1 (IFIH1/MDA5) is a cytosolic RIG-I-like receptor that couples recognition of duplex RNA to type I interferon induction. It has two N-terminal caspase activation and recruitment domains (CARDs), a central DExD/H-box helicase core with an inserted domain, and a zinc-binding C-terminal regulatory domain. Unlike RIG-I, which reads the end of a duplex, MDA5 binds the internal stem of long double-stranded RNA and polymerises head-to-tail along it; ATP binding and hydrolysis drive assembly and disassembly of these filaments, giving a proofreading mechanism that makes signalling depend on duplex length rather than on a chemical mark at the RNA end. Filament formation clusters the CARDs, which nucleate MAVS prion-like polymers on the mitochondrial outer membrane and activate TBK1/IKBKE and IRF3/IRF7, inducing interferon-alpha/beta and pro-inflammatory cytokines; MDA5 itself relocalises from cytosol to mitochondria upon activation and ISGylation. MDA5 is required for the response to picornaviruses such as encephalomyocarditis virus, and contributes to responses to coronaviruses, flaviviruses and some DNA viruses. Which RNA actually engages MDA5 during infection is unresolved. Long viral replicative duplexes and viral mRNA lacking the host 2'-O-methyl cap mark activate it, but crosslinking of endogenous MDA5 in SARS-CoV-2- and encephalomyocarditis-virus-infected cells recovers almost exclusively cellular RNA, concentrated in introns and near inverted Alu repeats, and infection-induced splicing defects are sufficient to trigger it; on that evidence MDA5 has been proposed to monitor the fidelity of host RNA processing rather than to detect a pathogen-specific molecular pattern. The same ambiguity is visible in disease: gain-of-function IFIH1 variants cause Aicardi-Goutieres syndrome and Singleton-Merten-spectrum type I interferonopathies through sterile activation, and adenosine-to-inosine editing by ADAR1 exists in part to prevent MDA5 from responding to endogenous duplex RNA. Common IFIH1 variants are associated with type 1 diabetes and other autoimmune conditions.

Disorders

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