IFIH1MDA5

Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and pro-inflammatory cytokines

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Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta.

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Upon viral RNA stimulation and ISGylation, translocates from cytosol to mitochondrion.

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The disease is caused by variants affecting the gene represented in this entry

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ATP + H2O = ADP + phosphate + H(+)

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Monomer in the absence of ligands and homodimerizes in the presence of dsRNA ligands. Can assemble into helical or linear polymeric filaments on long dsRNA. Interacts with MAVS/IPS1. Interacts (via the CARD domains) with TKFC, the interaction is inhibited by viral infection. Interacts with PCBP2. Interacts with NLRC5. Interacts with PIAS2-beta. Interacts with DDX60. Interacts with ANKRD17. Interacts with IKBKE. Interacts with ATG5 and ATG12, either as ATG5 and ATG12 monomers or as ATG12-ATG5 conjugates. Interacts with ZCCHC3; leading to activate IFIH1/MDA5. Interacts with RNF123. Interacts with DDX3X. Interacts with NOD1; this interaction promotes transcription of antiviral genes and inhibition of viral replication. Interacts with ECSIT; this interaction bridges IFIH1 to the MAVS complex at the mitochondrion

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(Microbial infection) Interacts with V protein of paramyxoviruses; these interactions prevent IFN-beta induction, and subsequent establishment of an antiviral state

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(Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction prevents the interaction of MAVS/IPS1 to IFIH1

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(Microbial infection) Interacts with Encephalomyocarditis virus protein 2C; this interaction inhibits the induction of the IFN-beta signal pathway

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(Microbial infection) Interacts with protease 3C of coxsackievirus A16; this interaction inhibits IFIH1 thereby attenuating type-I IFN production

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(Microbial infection) Interacts with SARS-COV-2 virus protein NSP3; the interaction antagonizes ISG15-dependent IFIH1 activation via active de-ISGylation

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(Microbial infection) Interacts with measles V protein; this interaction is involved in the inhibition of the host type I interferon signaling pathway by the virus

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By interferon (IFN) and TNF

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Type 1 diabetes mellitus 19 T1D19 A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility may be associated with variants affecting the gene represented in this entry MIM: 610155

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IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD)

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Singleton-Merten syndrome 1 SGMRT1 An autosomal dominant disorder with variable expression. Core features are marked aortic calcification, dental anomalies, osteopenia, acro-osteolysis, and to a lesser extent glaucoma, psoriasis, muscle weakness, and joint laxity. Dental anomalies include delayed eruption and immature root formation of anterior permanent teeth, early loss of permanent teeth due to short roots, acute root resorption, high caries, and aggressive alveolar bone loss. Additional clinical manifestations include particular facial characteristics and abnormal joint and muscle ligaments. The disease is caused by variants affecting the gene represented in this entry MIM: 182250

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Immunodeficiency 95 IMD95 An autosomal recessive disorder characterized by the onset of recurrent and severe viral respiratory infections in infancy or early childhood, and impaired interferon production during viral infection. The disease is caused by variants affecting the gene represented in this entry MIM: 619773

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Intracellular pattern recognition receptors MDA5, RIG-I, and LGP2 are essential components of the cellular response to virus infection and are homologous to the DEXH box subfamily of RNA helicases. However, the relevance of helicase activity in the regulation of interferon production remains elusive. To examine the importance of the helicase domain function for these signaling proteins, a series of mutations targeting conserved helicase sequence motifs were analyzed for enzymatic activity, RNA binding, interferon induction, and antiviral signaling. Results indicate that all targeted motifs are required for ATP hydrolysis, but a subset is involved in RNA binding. The enzymatically inactive mutants differed in their signaling ability. Notably, mutations to MDA5 motifs I, III, and VI and RIG-I motif III produced helicase proteins with constitutive antiviral activity, whereas mutations in RIG-I motif V retained ATP hydrolysis but failed to mediate signal transduction. These findings demonstrate that type I interferon production mediated by full-length MDA5 and RIG-I is independent of the helicase domain catalytic activity. In addition, neither enzymatic activity nor RNA binding was required for negative regulation of antiviral signaling by LGP2, supporting an RNA-independent interference mechanism.

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