MDA5

Interferon induced with helicase C domain 1
Rendering based on PDB 2RQB​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2RQB​, 3B6E​, 3GA3​, 4GL2​
Identifiers
Symbols	IFIH1 ; AGS7; Hlcd; IDDM19; MDA-5; MDA5; RLR-2; SGMRT1
External IDs	OMIM: 606951 MGI: 1918836 HomoloGene: 32535 GeneCards: IFIH1 Gene
EC number	3.6.4.13
Gene ontology Molecular function • DNA binding • double-stranded RNA binding • single-stranded RNA binding • helicase activity • protein binding • ATP binding • zinc ion binding • ribonucleoprotein complex binding Cellular component • nucleus • cytosol Biological process • detection of virus • response to virus • viral process • protein sumoylation • negative regulation of type I interferon production • positive regulation of interferon-alpha production • positive regulation of interferon-beta production • regulation of type III interferon production • cytoplasmic pattern recognition receptor signaling pathway in response to virus • MDA-5 signaling pathway • innate immune response Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	64135	71586
Ensembl	ENSG00000115267	ENSMUSG00000026896
UniProt	Q9BYX4	Q8R5F7
RefSeq (mRNA)	NM_022168	NM_001164477
RefSeq (protein)	NP_071451	NP_001157949
Location (UCSC)	Chr 2: 162.27 – 162.32 Mb	Chr 2: 62.6 – 62.65 Mb
PubMed search

MDA5 (Melanoma Differentiation-Associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that in humans is encoded by the IFIH1 gene.^[1] MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and functions as a pattern recognition receptor (recognizing dsRNA) that is a sensor for viruses. MDA5 typically recognizes dsRNA that is over 2000nts in length.^[2] For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2.^[3] The signaling cascades in MDA5 is initiated via CARD domain.^[4]

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein that is upregulated in response to treatment with beta-interferon (IFNB) and a protein kinase C-activating compound, mezerein (MEZ). Irreversible reprogramming of melanomas can be achieved by treatment with both these agents; treatment with either agent alone only achieves reversible differentiation.^[1]

Clinical significance

Mutations in IFIH1/MDA5 are associated to Singleton-Merten Syndrome ^[5] and to Aicardi–Goutières syndrome.

Antibodies against MDA5 are associated to amyopathic dermatomyositis with rapidly progressive interstitial lung disease.

References

1. "Entrez Gene: IFIH1 interferon induced with helicase C domain 1".
2. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S.; Takeuchi; Mikamo-Satoh; Hirai; Kawai; Matsushita; Hiiragi; Dermody; Fujita; Akira (Jul 2008). "Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5". J Exp Med. 205 (7): 1601–1610. doi:10.1084/jem.20080091. PMC 2442638. PMID 18591409.
3. Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O; Kato; Kumagai; Yoneyama; Sato; Matsushita; Tsujimura; Fujita; Akira; Takeuchi (January 2010). "LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses". Proc. Natl. Acad. Sci. U.S.A. 107 (4): 1512–7. Bibcode:2010PNAS..107.1512S. doi:10.1073/pnas.0912986107. PMC 2824407. PMID 20080593.
4. Takeuchi, O; Akira, S (2008). "MDA5/RIG-I and virus recognition". Current Opinion in Immunology 20 (1): 17–22. doi:10.1016/j.coi.2008.01.002. PMID 18272355.
5. Rutsch, F; MacDougall, M; Lu, C; Buers, I; Mamaeva, O; Nitschke, Y; Rice, G. I.; Erlandsen, H; Kehl, H. G.; Thiele, H; Nürnberg, P; Höhne, W; Crow, Y. J.; Feigenbaum, A; Hennekam, R. C. (2015). "A Specific IFIH1 Gain-of-function Mutation Causes Singleton-Merten Syndrome". The American Journal of Human Genetics 96: 275–82. doi:10.1016/j.ajhg.2014.12.014. PMID 25620204.

Further reading

• Kang DC, Gopalkrishnan RV, Wu Q, et al. (2002). "mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties". Proc. Natl. Acad. Sci. U.S.A. 99 (2): 637–642. doi:10.1073/pnas.022637199. PMC 117358. PMID 11805321.
• Kovacsovics M, Martinon F, Micheau O, et al. (2002). "Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation". Curr. Biol. 12 (10): 838–843. doi:10.1016/S0960-9822(02)00842-4. PMID 12015121.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Cocude C, Truong MJ, Billaut-Mulot O, et al. (2004). "A novel cellular RNA helicase, RH116, differentially regulates cell growth, programmed cell death and human immunodeficiency virus type 1 replication". J. Gen. Virol. 84 (Pt 12): 3215–3225. doi:10.1099/vir.0.19300-0. PMID 14645903.
• Kang DC, Gopalkrishnan RV, Lin L, et al. (2004). "Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene". Oncogene 23 (9): 1789–1800. doi:10.1038/sj.onc.1207300. PMID 14676839.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–45. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–2127. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Andrejeva J, Childs KS, Young DF, et al. (2005). "The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter". Proc. Natl. Acad. Sci. U.S.A. 101 (49): 17264–17269. doi:10.1073/pnas.0407639101. PMC 535396. PMID 15563593.
• Yoneyama M, Kikuchi M, Matsumoto K, et al. (2005). "Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity". J. Immunol. 175 (5): 2851–8. doi:10.4049/jimmunol.175.5.2851. PMID 16116171.
• Kawai T, Takahashi K, Sato S, et al. (2005). "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction". Nat. Immunol. 6 (10): 981–988. doi:10.1038/ni1243. PMID 16127453.
• Meylan E, Curran J, Hofmann K, et al. (2005). "Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus". Nature 437 (7062): 1167–1172. doi:10.1038/nature04193. PMID 16177806.
• Lin L, Su Z, Lebedeva IV, et al. (2006). "Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis". Cell Death Differ. 13 (11): 1982–1993. doi:10.1038/sj.cdd.4401899. PMID 16575407.
• Smyth DJ, Cooper JD, Bailey R, et al. (2006). "A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region". Nat. Genet. 38 (6): 617–619. doi:10.1038/ng1800. PMID 16699517.
• Berghäll H, Sirén J, Sarkar D, et al. (2007). "The interferon-inducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines". Microbes Infect. 8 (8): 2138–2144. doi:10.1016/j.micinf.2006.04.005. PMID 16782388.
• Sirén J, Imaizumi T, Sarkar D, et al. (2007). "Retinoic acid inducible gene-I and mda-5 are involved in influenza A virus-induced expression of antiviral cytokines". Microbes Infect. 8 (8): 2013–2020. doi:10.1016/j.micinf.2006.02.028. PMID 16797201.
• Barral PM, Morrison JM, Drahos J, et al. (2007). "MDA-5 is cleaved in poliovirus-infected cells". J. Virol. 81 (8): 3677–3684. doi:10.1128/JVI.01360-06. PMC 1866155. PMID 17267501.
• Marinou I, Montgomery DS, Dickson MC, et al. (2007). "The interferon induced with helicase domain 1 A946T polymorphism is not associated with rheumatoid arthritis". Arthritis Research & Therapy 9 (2): R40. doi:10.1186/ar2179. PMC 1906818. PMID 17442111.
• Sutherland A, Davies J, Owen CJ, et al. (2007). "Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves' disease susceptibility". J. Clin. Endocrinol. Metab. 92 (8): 3338–3341. doi:10.1210/jc.2007-0173. PMID 17535987.
• Matsukura S, Kokubu F, Kurokawa M, et al. (2007). "Role of RIG-I, MDA-5, and PKR on the expression of inflammatory chemokines induced by synthetic dsRNA in airway epithelial cells". Int. Arch. Allergy Immunol. 143 Suppl 1: 80–83. doi:10.1159/000101411. PMID 17541283.