MDA5

MDA5 (melanoma differentiation-associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the IFIH1 gene in humans.{{cite web | title = Entrez Gene: IFIH1 interferon induced with helicase C domain 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=64135}} 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 capable of detecting viruses. It is generally believed that MDA5 recognizes double stranded RNA (dsRNA) over 2000nts in length,{{cite journal | vauthors = Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S | title = Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5 | journal = The Journal of Experimental Medicine | volume = 205 | issue = 7 | pages = 1601–10 | date = July 2008 | pmid = 18591409 | pmc = 2442638 | doi = 10.1084/jem.20080091 }} however it has been shown that whilst MDA5 can detect and bind to cytoplasmic dsRNA, it is also activated by a high molecular weight RNA complex composed of ssRNA and dsRNA.{{cite journal | vauthors = Pichlmair A, Schulz O, Tan CP, Rehwinkel J, Kato H, Takeuchi O, Akira S, Way M, Schiavo G, Reis e Sousa C | title = Activation of MDA5 requires higher-order RNA structures generated during virus infection | journal = Journal of Virology | volume = 83 | issue = 20 | pages = 10761–9 | date = October 2009 | pmid = 19656871 | pmc = 2753146 | doi = 10.1128/JVI.00770-09 }} For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2.{{cite journal | vauthors = Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O | title = LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 4 | pages = 1512–7 | date = January 2010 | pmid = 20080593 | pmc = 2824407 | doi = 10.1073/pnas.0912986107 | bibcode = 2010PNAS..107.1512S | doi-access = free }} The signaling cascades in MDA5 is initiated via CARD domain.{{cite journal | vauthors = Takeuchi O, Akira S | title = MDA5/RIG-I and virus recognition | journal = Current Opinion in Immunology | volume = 20 | issue = 1 | pages = 17–22 | date = February 2008 | pmid = 18272355 | doi = 10.1016/j.coi.2008.01.002 }} Some observations made in cancer cells show that MDA5 also interacts with cellular RNA is able to induce an autoinflammatory response.{{cite journal | vauthors = Dias Junior AG, Sampaio NG, Rehwinkel J | title = A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation | journal = Trends in Microbiology | volume = 27 | issue = 1 | pages = 75–85 | date = January 2019 | pmid = 30201512 | doi = 10.1016/j.tim.2018.08.007 | pmc = 6319154 | url = }}

Function

= As a pattern recognition receptor =

MDA5 is able to detect long dsRNA, the genomic RNA of dsRNA viruses as well as replicative intermediates of both positive and negative sense RNA viruses.{{cite journal | vauthors = Wu B, Peisley A, Richards C, Yao H, Zeng X, Lin C, Chu F, Walz T, Hur S | title = Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5 | language = en | journal = Cell | volume = 152 | issue = 1–2 | pages = 276–89 | date = January 2013 | pmid = 23273991 | doi = 10.1016/j.cell.2012.11.048 | doi-access = free }} MDA5 has also been shown to interact with a number of chemical modifications of RNA. The eukaryotic messenger RNA, for example, is often methylated at the 2′-O position of the first and second nucleotide behind the 5′ cap.{{cite journal | vauthors = Werner M, Purta E, Kaminska KH, Cymerman IA, Campbell DA, Mittra B, Zamudio JR, Sturm NR, Jaworski J, Bujnicki JM | title = 2′-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family | journal = Nucleic Acids Research | volume = 39 | issue = 11 | pages = 4756–68 | date = June 2011 | pmid = 21310715 | doi = 10.1093/nar/gkr038 | pmc = 3113572 | url = }} These structures are termed cap1 and cap2 respectively.{{cite journal | vauthors = Byszewska M, Śmietański M, Purta E, Bujnicki JM | title = RNA methyltransferases involved in 5′ cap biosynthesis | journal = RNA Biology | volume = 11 | issue = 12 | pages = 1597–607 | date = 2014-12-02 | pmid = 25626080 | pmc = 4615557 | doi = 10.1080/15476286.2015.1004955 }} MDA5 is able to detect the absence of the 2′-O-methylation, bind to this type of RNA and initiate an immune response.{{cite journal | vauthors = Züst 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 | title = Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5 | journal = Nature Immunology | volume = 12 | issue = 2 | pages = 137–43 | date = February 2011 | pmid = 21217758 | doi = 10.1038/ni.1979 | pmc = 3182538 }}

== Mechanism ==

Activated MDA5 interacts with the mitochondrial antiviral signalling proteins (MAVS) through its caspase activation and recruitment domains (CARDs) at the N-terminus.{{cite journal | vauthors = Reikine S, Nguyen JB, Modis Y | title = Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5 | language = en | journal = Frontiers in Immunology | volume = 5 | pages = 342 | date = 2014 | pmid = 25101084 | doi = 10.3389/fimmu.2014.00342 | pmc = 4107945 | doi-access = free }} The MAVS then work as a multiprotein complex to recruit the inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) along with the serine/threonine-protein kinase 1 (TBK1).{{cite journal | vauthors = Fang R, Jiang Q, Zhou X, Wang C, Guan Y, Tao J, Xi J, Feng JM, Jiang Z | title = MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner | journal = PLOS Pathogens | volume = 13 | issue = 11 | pages = e1006720 | date = November 2017 | pmid = 29125880 | pmc = 5699845 | doi = 10.1371/journal.ppat.1006720 | doi-access = free }} This causes the phosphorylation and the transport of the interferon regulatory factors 3 and 7 (IRF3 and IRF7) into the cell's nucleus. Once there, the regulatory factors induce the transcription of type I interferon genes IFN-β and IFN-α.{{cite journal | vauthors = Brisse M, Ly H | title = Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5 | language = en | journal = Frontiers in Immunology | volume = 10 | pages = 1586 | date = 2019 | pmid = 31379819 | doi = 10.3389/fimmu.2019.01586 | pmc = 6652118 | doi-access = free }}

Structure

MDA5 is classified as an ATP-dependent DExD/H box RNA helicase. It comprises 2 CARD domains located at the N-terminus, a hinge region and the helicase domain which is made up of the domains RecA-like Hel1 and Hel2.{{cite journal | vauthors = Rawling DC, Pyle AM | title = Parts, assembly and operation of the RIG-I family of motors | journal = Current Opinion in Structural Biology | volume = 25 | pages = 25–33 | date = April 2014 | pmid = 24878341 | pmc = 4070197 | doi = 10.1016/j.sbi.2013.11.011 }} Another hinge region connects the C-terminal domain (CTD) which is responsible for the recognition and the binding of RNA.{{cite journal | vauthors = Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T | title = The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses | journal = Nature Immunology | volume = 5 | issue = 7 | pages = 730–7 | date = July 2004 | pmid = 15208624 | doi = 10.1038/ni1087 | s2cid = 34876422 | url = http://www.nature.com/articles/ni1087 }} Apart from the positively charged groove recognizing the RNA, the CTD also contains a zinc binding domain.{{cite journal | vauthors = Cui S, Eisenächer K, Kirchhofer A, Brzózka K, Lammens A, Lammens K, Fujita T, Conzelmann KK, Krug A, Hopfner KP | title = The C-terminal regulatory domain is the RNA 5'-triphosphate sensor of RIG-I | journal = Molecular Cell | volume = 29 | issue = 2 | pages = 169–79 | date = February 2008 | pmid = 18243112 | doi = 10.1016/j.molcel.2007.10.032 | url = https://www.dora.lib4ri.ch/psi/islandora/object/psi%3A18443 | doi-access = free }}

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 (IFN-β) 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.

Clinical significance

Mutations in IFIH1/MDA5 are associated to Singleton-Merten Syndrome{{cite journal | vauthors = Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nürnberg P, Höhne W, Crow YJ, Feigenbaum A, Hennekam RC | title = A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome | journal = American Journal of Human Genetics | volume = 96 | issue = 2 | pages = 275–82 | date = February 2015 | pmid = 25620204 | pmc = 4320263 | doi = 10.1016/j.ajhg.2014.12.014 }} and to Aicardi–Goutières syndrome.

Some IFIH1 SNPs are associated with increased risk of type 1 diabetes.{{cite journal | vauthors = Oram RA, Patel K, Hill A, Shields B, McDonald TJ, Jones A, Hattersley AT, Weedon MN | title = A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults | journal = Diabetes Care | volume = 39 | issue = 3 | pages = 337–44 | date = March 2016 | pmid = 26577414 | pmc = 5642867 | doi = 10.2337/dc15-1111 }}

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

References

External links

{{PDBe-KB2|Q9BYX4|Interferon-induced helicase C domain-containing protein 1}}

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Category:RIG-I-like receptors

Category:Intracellular receptors