6h66

Structural highlights

Function

IFIH1_MOUSE 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. 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), mengo encephalomyocarditis virus (ENMG), and theiler's murine encephalomyelitis virus (TMEV). 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.^{[1] [2] [3] [4] [5]}

References

1. ↑ Kovacsovics M, Martinon F, Micheau O, Bodmer JL, Hofmann K, Tschopp J. Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr Biol. 2002 May 14;12(10):838-43. PMID:12015121
2. ↑ Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006 May 4;441(7089):101-5. Epub 2006 Apr 9. PMID:16625202 doi:http://dx.doi.org/nature04734
3. ↑ Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, Akira S, Gill MA, Garcia-Sastre A, Katze MG, Gale M Jr. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol. 2008 Jan;82(1):335-45. Epub 2007 Oct 17. PMID:17942531 doi:http://dx.doi.org/10.1128/JVI.01080-07
4. ↑ Pichlmair A, Schulz O, Tan CP, Rehwinkel J, Kato H, Takeuchi O, Akira S, Way M, Schiavo G, Reis e Sousa C. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol. 2009 Oct;83(20):10761-9. doi: 10.1128/JVI.00770-09. Epub 2009 Aug 5. PMID:19656871 doi:10.1128/JVI.00770-09
5. ↑ Zust R, Cervantes-Barragan L, Habjan M, Maier R, Neuman BW, Ziebuhr J, Szretter KJ, Baker SC, Barchet W, Diamond MS, Siddell SG, Ludewig B, Thiel V. Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol. 2011 Feb;12(2):137-43. doi: 10.1038/ni.1979. Epub 2011 Jan 9. PMID:21217758 doi:10.1038/ni.1979
6. ↑ Yu Q, Qu K, Modis Y. Cryo-EM Structures of MDA5-dsRNA Filaments at Different Stages of ATP Hydrolysis. Mol Cell. 2018 Nov 7. pii: S1097-2765(18)30844-X. doi:, 10.1016/j.molcel.2018.10.012. PMID:30449722 doi:http://dx.doi.org/10.1016/j.molcel.2018.10.012