IFIH1

IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome.

interferon induced with helicase C domain 1

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 proinflammatory cytokines (PubMed:33727702).

Its ligands include mRNA lacking 2'-O-methylation at their 5' cap and long-dsRNA (>1 kb in length). 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. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV) and mengo encephalomyocarditis virus (ENMG). Detects coronavirus SARS-CoV-2 (PubMed:33440148, PubMed:33514628).

Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines.

Cellular response to exogenous dsRNA Source: UniProtKB
Cellular response to virus Source: ARUK-UCL
Cytoplasmic pattern recognition receptor signaling pathway in response to virus Source: UniProtKB
Defense response to virus Source: UniProtKB
Detection of virus Source: BHF-UCL
Innate immune response Source: GO_Central
MDA-5 signaling pathway Source: UniProtKB
Negative regulation of viral genome replication Source: UniProtKB
Positive regulation of interferon-alpha production Source: UniProtKB
Positive regulation of interferon-beta production Source: UniProtKB
Positive regulation of interleukin-6 production Source: UniProtKB
Positive regulation of response to cytokine stimulus Source: UniProtKB
Positive regulation of tumor necrosis factor production Source: UniProtKB
Protein sumoylation Source: UniProtKB
Regulation of type III interferon production Source: UniProtKB
Response to virus Source: UniProtKB

Cytoplasm; Mitochondrion; Nucleus. Upon viral RNA stimulation and ISGylation, translocates from cytosol to mitochondrion. May be found in the nucleus, during apoptosis.

Diabetes mellitus, insulin-dependent, 19 (IDDM19):
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. 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).
Aicardi-Goutieres syndrome 7 (AGS7):
A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.
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.

Sumoylated. Sumoylation positively regulates its role in type I interferon induction and is enhanced by PIAS2-beta.
Ubiquitinated by RNF125, leading to its degradation by the proteasome (PubMed:17460044). USP17/UPS17L2-dependent deubiquitination positively regulates the receptor (PubMed:20368735). Ubiquitinated by TRIM25 via 'Lys-63'-linked ubiquitination, promoting activation of IFIH1/MDA5 (PubMed:30193849). Ubiquitinated by TRIM40 via 'Lys-48'-linked ubiquitination; leading to proteasomal degradation (PubMed:29117565).
ISGylated by ISG15. ISGylation increases upon infection with dengue (DENV) or Zika (ZIKV) viruses. ISGylation at Lys-23 and Lys-43 is dependent of dephosphorylation at Ser-88, regulates mitochondrial translocation and oligomerization. Essential for IFIH1/MDA5-mediated cytokine responses and restriction of virus replication.
Phosphorylated at Ser-88. Dephosphorylated by phsophatases PP1; dephosphorylation precedes and is required for ISGylation.
During apoptosis, processed into 3 cleavage products. The helicase-containing fragment, once liberated from the CARD domains, translocate from the cytoplasm to the nucleus. The processed protein significantly sensitizes cells to DNA degradation.By similarity
(Microbial infection) Cleaved and inactivated by the protease 2A of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production.