MDA5

Last updated


IFIH1
Protein IFIH1 PDB 2RQB.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IFIH1 , AGS7, Hlcd, IDDM19, MDA-5, MDA5, RLR-2, SGMRT1, interferon induced with helicase C domain 1, IMD95
External IDs OMIM: 606951 MGI: 1918836 HomoloGene: 32535 GeneCards: IFIH1
Orthologs
SpeciesHumanMouse
Entrez

64135

71586

Ensembl

ENSG00000115267

ENSMUSG00000026896

UniProt

Q9BYX4

Q8R5F7

RefSeq (mRNA)

NM_022168

NM_001164477
NM_027835

RefSeq (protein)

NP_071451

NP_001157949
NP_082111

Location (UCSC) Chr 2: 162.27 – 162.32 Mb Chr 2: 62.43 – 62.48 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

MDA5 (melanoma differentiation-associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the IFIH1 gene in humans. [5] 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, [6] 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. [7] For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2. [8] The signaling cascades in MDA5 is initiated via CARD domain. [9] Some observations made in cancer cells show that MDA5 also interacts with cellular RNA is able to induce an autoinflammatory response. [10]

Contents

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. [11] 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. [12] These structures are termed cap1 and cap2 respectively. [13] MDA5 is able to detect the absence of the 2′-O-methylation, bind to this type of RNA and initiate an immune response. [14]

Mechanism

Activated MDA5 interacts with the mitochondrial antiviral signalling proteins (MAVS) through its caspase activation and recruitment domains (CARDs) at the N-terminus. [15] 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). [16] 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. [17]

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. [18] Another hinge region connects the C-terminal domain (CTD) which is responsible for the recognition and the binding of RNA. [19] Apart from the positively charged groove recognizing the RNA, the CTD also contains a zinc binding domain. [20]

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. [5]

Clinical significance

Mutations in IFIH1/MDA5 are associated to Singleton-Merten Syndrome [21] and to Aicardi–Goutières syndrome.

Some IFIH1 SNPs are associated with increased risk of type 1 diabetes. [22]

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

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<span class="mw-page-title-main">Toll-like receptor 3</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 3 (TLR3) also known as CD283 is a protein that in humans is encoded by the TLR3 gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune system. TLR3 recognizes double-stranded RNA in endosomes, which is a common feature of viral genomes internalised by macrophages and dendritic cells.

<span class="mw-page-title-main">Ribonuclease L</span> Enzyme found in humans

Ribonuclease L or RNase L, known sometimes as ribonuclease 4 or 2'-5' oligoadenylate synthetase-dependent ribonuclease, is an interferon (IFN)-induced ribonuclease which, upon activation, destroys all RNA within the cell. RNase L is an enzyme that in humans is encoded by the RNASEL gene.

<span class="mw-page-title-main">CARD (domain)</span> Interaction motifs found in a wide array of proteins

Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARDs are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.

The NS1 influenza protein (NS1) is a viral nonstructural protein encoded by the NS gene segments of type A, B and C influenza viruses. Also encoded by this segment is the nuclear export protein (NEP), formally referred to as NS2 protein, which mediates the export of influenza virus ribonucleoprotein (RNP) complexes from the nucleus, where they are assembled.

<span class="mw-page-title-main">Protein kinase R</span> Human protein and coding gene

Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long.

<span class="mw-page-title-main">Interferon-alpha/beta receptor</span> Heterodimeric receptor

The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ.

<span class="mw-page-title-main">ISG15</span> Protein-coding gene in the species Homo sapiens

Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene. ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellular protein modifier. The precise functions are diverse and vary among species but include potentiation of Interferon gamma (IFN-II) production in lymphocytes, ubiquitin-like conjugation to newly-synthesized proteins and negative regulation of the IFN-I response.

<span class="mw-page-title-main">RIG-I</span> Mammalian protein found in humans

RIG-I is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus. These viruses can include West Nile virus, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and coronaviruses.

<span class="mw-page-title-main">ADAR</span> Mammalian protein found in Homo sapiens

The double-stranded RNA-specific adenosine deaminase enzyme family are encoded by the ADAR family genes. ADAR stands for adenosine deaminase acting on RNA. This article focuses on the ADAR proteins; This article details the evolutionary history, structure, function, mechanisms and importance of all proteins within this family.

<span class="mw-page-title-main">DDX3X</span> Protein-coding gene in humans

ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene.

<span class="mw-page-title-main">RARRES3</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor responder protein 3 is a protein that in humans is encoded by the RARRES3 gene.

<span class="mw-page-title-main">Mitochondrial antiviral-signaling protein</span> Protein-coding gene in the species Homo sapiens

Mitochondrial antiviral-signaling protein (MAVS) is a protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and mitochondrial-associated endoplasmic reticulum membrane (MAM). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating MAVS. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host's virally infected cells, resulting in clearance of the virus.

<span class="mw-page-title-main">LGP2</span> Protein-coding gene in the species Homo sapiens

Probable ATP-dependent RNA helicase DHX58 also known as RIG-I-like receptor 3 (RLR-3) or RIG-I-like receptor LGP2 (RLR) is a RIG-I-like receptor dsRNA helicase enzyme that in humans is encoded by the DHX58 gene. The protein encoded by the gene DHX58 is known as LGP2.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

<span class="mw-page-title-main">AIM2</span> Protein-coding gene in the species Homo sapiens

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.

RIG-I-like receptors are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system. RIG-I is the best characterized receptor within the RIG-I like receptor (RLR) family. Together with MDA5 and LGP2, this family of cytoplasmic pattern recognition receptors (PRRs) are sentinels for intracellular viral RNA that is a product of viral infection. The RLR receptors provide frontline defence against viral infections in most tissues.

<span class="mw-page-title-main">Stimulator of interferon genes</span> Protein-coding gene in the species Homo sapiens

Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a protein that in humans is encoded by the STING1 gene.

An interferon-stimulated gene (ISG) is a gene that can be expressed in response to stimulation by interferon. Interferons bind to receptors on the surface of a cell, initiating protein signaling pathways within the cell. This interaction leads to the expression of a subset of genes involved in the innate immune system response. ISGs are commonly expressed in response to viral infection, but also during bacterial infection and in the presence of parasites.It's currently estimated that 10% of the human genome is regulated by interferons (IFNs). Interferon stimulated genes can act as an initial response to pathogen invasion, slowing down viral replication and increasing expression of immune signaling complexes. There are three known types of interferon. With approximately 450 genes highly expressed in response to interferon type I. Type I interferon consists of INF-α, INF-β, INF-ω and is expressed in response to viral infection. ISGs induced by type I interferon are associated with viral replication suppression and increase expression of immune signaling proteins. Type II interferon consists only of INF-γ and is associated with controlling intracellular pathogens and tumor suppressor genes. Type III interferon consists of INF-λ and is associated with viral immune response and is key in anti-fungal neutrophil response.

<span class="mw-page-title-main">Viral strategies for immune response evasion</span>

The mammalian immune system has evolved complex methods for addressing and adapting to foreign antigens. At the same time, viruses have co-evolved evasion machinery to address the many ways that host organisms attempt to eradicate them. DNA and RNA viruses use complex methods to evade immune cell detection through disruption of the Interferon Signaling Pathway, remodeling of cellular architecture, targeted gene silencing, and recognition protein cleavage.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115267 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026896 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: IFIH1 interferon induced with helicase C domain 1".
  6. ↑ Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, et al. (July 2008). "Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5". The Journal of Experimental Medicine. 205 (7): 1601–10. doi:10.1084/jem.20080091. PMC   2442638 . PMID   18591409.
  7. ↑ Pichlmair A, Schulz O, Tan CP, Rehwinkel J, Kato H, Takeuchi O, et al. (October 2009). "Activation of MDA5 requires higher-order RNA structures generated during virus infection". Journal of Virology. 83 (20): 10761–9. doi:10.1128/JVI.00770-09. PMC   2753146 . PMID   19656871.
  8. ↑ Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, et al. (January 2010). "LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses". Proceedings of the National Academy of Sciences of the United States of America. 107 (4): 1512–7. Bibcode:2010PNAS..107.1512S. doi: 10.1073/pnas.0912986107 . PMC   2824407 . PMID   20080593.
  9. ↑ Takeuchi O, Akira S (February 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.
  10. ↑ Dias Junior AG, Sampaio NG, Rehwinkel J (January 2019). "A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation". Trends in Microbiology. 27 (1): 75–85. doi:10.1016/j.tim.2018.08.007. PMC   6319154 . PMID   30201512.
  11. ↑ Wu B, Peisley A, Richards C, Yao H, Zeng X, Lin C, et al. (January 2013). "Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5". Cell. 152 (1–2): 276–89. doi: 10.1016/j.cell.2012.11.048 . PMID   23273991.
  12. ↑ Werner M, Purta E, Kaminska KH, Cymerman IA, Campbell DA, Mittra B, et al. (June 2011). "2′-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family". Nucleic Acids Research. 39 (11): 4756–68. doi:10.1093/nar/gkr038. PMC   3113572 . PMID   21310715.
  13. ↑ Byszewska M, Śmietański M, Purta E, Bujnicki JM (2014-12-02). "RNA methyltransferases involved in 5′ cap biosynthesis". RNA Biology. 11 (12): 1597–607. doi:10.1080/15476286.2015.1004955. PMC   4615557 . PMID   25626080.
  14. ↑ Züst R, Cervantes-Barragan L, Habjan M, Maier R, Neuman BW, Ziebuhr J, et al. (February 2011). "Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5". Nature Immunology. 12 (2): 137–43. doi:10.1038/ni.1979. PMC   3182538 . PMID   21217758.
  15. ↑ Reikine S, Nguyen JB, Modis Y (2014). "Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5". Frontiers in Immunology. 5: 342. doi: 10.3389/fimmu.2014.00342 . PMC   4107945 . PMID   25101084.
  16. ↑ Fang R, Jiang Q, Zhou X, Wang C, Guan Y, Tao J, et al. (November 2017). "MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner". PLOS Pathogens. 13 (11): e1006720. doi: 10.1371/journal.ppat.1006720 . PMC   5699845 . PMID   29125880.
  17. ↑ Brisse M, Ly H (2019). "Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5". Frontiers in Immunology. 10: 1586. doi: 10.3389/fimmu.2019.01586 . PMC   6652118 . PMID   31379819.
  18. ↑ Rawling DC, Pyle AM (April 2014). "Parts, assembly and operation of the RIG-I family of motors". Current Opinion in Structural Biology. 25: 25–33. doi:10.1016/j.sbi.2013.11.011. PMC   4070197 . PMID   24878341.
  19. ↑ Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. (July 2004). "The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses". Nature Immunology. 5 (7): 730–7. doi:10.1038/ni1087. PMID   15208624. S2CID   34876422.
  20. ↑ Cui S, Eisenächer K, Kirchhofer A, Brzózka K, Lammens A, Lammens K, et al. (February 2008). "The C-terminal regulatory domain is the RNA 5'-triphosphate sensor of RIG-I". Molecular Cell. 29 (2): 169–79. doi: 10.1016/j.molcel.2007.10.032 . PMID   18243112.
  21. ↑ Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, et al. (February 2015). "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome". American Journal of Human Genetics. 96 (2): 275–82. doi:10.1016/j.ajhg.2014.12.014. PMC   4320263 . PMID   25620204.
  22. ↑ Oram RA, Patel K, Hill A, Shields B, McDonald TJ, Jones A, et al. (March 2016). "A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults". Diabetes Care. 39 (3): 337–44. doi:10.2337/dc15-1111. PMC   5642867 . PMID   26577414.

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