RIG-I

Last updated
DDX58
Protein DDX58 PDB 2QFB.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DDX58 , DEAD (Asp-Glu-Ala-Asp) box polypeptide 58, RIGI, RLR-1, SGMRT2, RIG-I, DEXD/H-box helicase 58, RIG1
External IDs OMIM: 609631; MGI: 2442858; HomoloGene: 32215; GeneCards: DDX58; OMA:DDX58 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

23586

230073

Ensembl

ENSG00000107201

ENSMUSG00000040296

UniProt

O95786

Q6Q899

RefSeq (mRNA)

NM_014314

NM_172689

RefSeq (protein)

NP_055129

NP_766277

Location (UCSC) Chr 9: 32.46 – 32.53 Mb Chr 4: 40.2 – 40.24 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. [5] 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. [5] [6]

RIG-I is an ATP-dependent DExD/H box RNA helicase that is activated by immunostimulatory RNAs from viruses as well as RNAs of other origins. RIG-I recognizes short double-stranded RNA (dsRNA) in the cytosol with a 5' tri- or di-phosphate end or a 5' 7-methyl guanosine (m7G) cap (cap-0), but not RNA with a 5' m7G cap having a ribose 2′-O-methyl modification (cap-1). [7] [8] These are often generated during a viral infection but can also be host-derived. [5] [9] [10] [11] [12] Once activated by the dsRNA, the N-terminus caspase activation and recruitment domains (CARDs) migrate and bind with CARDs attached to mitochondrial antiviral signaling protein (MAVS) to activate the signaling pathway for IFN1. [5] [9]

Type-I IFNs have three main functions: to limit the virus from spreading to nearby cells, promote an innate immune response, including inflammatory responses, and help activate the adaptive immune system. [13] Other studies have shown that in different microenvironments, such as in cancerous cells, RIG-I has more functions other than viral recognition. [10] RIG-I orthologs are found in mammals, geese, ducks, some fish, and some reptiles. [9] RIG-I is in most cells, including various innate immune system cells, and is usually in an inactive state. [5] [9] Knockout mice that have been designed to have a deleted or non-functioning RIG-I gene are not healthy and typically die embryonically. If they survive, the mice have serious developmental dysfunction. [9] The stimulator of interferon genes STING antagonizes RIG-I by binding its N-terminus, probably as to avoid overactivation of RIG-I signaling and the associated autoimmunity. [14]

Structure

This image shows the basic structure of RIG-I while it is inactive and active. Shown are the N-terminus CARDs, the DExD/H helicase domain, and the C-terminus repressor domain (RD). Included on the active structure is the most common RIG-I PAMP, dsRNA with a 5' triphosphate (5'ppp). RIG-I active and inactive.jpg
This image shows the basic structure of RIG-I while it is inactive and active. Shown are the N-terminus CARDs, the DExD/H helicase domain, and the C-terminus repressor domain (RD). Included on the active structure is the most common RIG-I PAMP, dsRNA with a 5' triphosphate (5'ppp).

RIG-I is encoded by the DDX58 gene in humans. [9] [15] RIG-I is a helical ATP-dependent DExD/H box RNA helicase with a repressor domain (RD) on the C-terminus that binds to the target RNA. [5] [9] Included on the N-terminus are two caspase activation and recruitment domains (CARDs) that are important for interactions with mitochondrial antiviral signaling protein (MAVS). [5] [9] RIG-I is a member of the RIG-I like receptors (RLRs) that also includes Melanoma Differentiation-Associated protein 5 (MDA5) and Laboratory of genetics physiology 2 (LGP2). [5] [9] RIG-I and MDA5 are both involved in activating MAVS and triggering an antiviral response. [16]

Functions

As a Pattern Recognition Receptor

Pattern Recognition Receptors

Pattern Recognition Receptors (PRRs) are a part of the innate immune system used for recognizing invaders. [17] In a viral infection, a virus enters a cell, and it takes over the cell's machinery to self replicate. Once a virus has begun replication, the infected cell is no longer useful and potentially harmful to its host, and the host's immune system must be notified. RIG-I functions as a pattern recognition receptor and PRR's are the molecules that start the notification process. PRRs recognize specific Pathogen-Associated Molecular Patterns (PAMP). [17] Once the PAMP is recognized, it can then lead to a signaling cascade producing an inflammatory response or an interferon response. PRRs are located in many different cell types, however most notably active in the innate immune system cells. In addition, they are located in many different parts of those cells, such as the cell membrane, endosomal membrane, and in the cytosol, to provide the most protection against many types of invaders (i.e., extracellular and intracellular microbes). [5]

RIG-I PAMPs

RIG-I is located in the cytoplasm where its function is to recognize its PAMP, which are ideally short (<300 base pairs) dsRNA with a 5′ triphosphate (5′ ppp). [5] [9] However, it has been noted that while not ideal, and response is weakened, RIG-I can recognize 5′ diphosphate (5′pp). This ability is important as many viruses have evolved to evade RIG-I, so having the dual ligand opens up more doors for recognition. [5] [9] An example of viruses evolving to evade RIG-I is in the case of certain retroviruses, such as HIV-1, encode a protease that directs RIG-I to the lysosome for degradation, and thereby evade RIG-I mediated signaling. [6] The dsRNA can come from single-stranded RNA (ssRNA) viruses or from dsRNA viruses. The ssRNA viruses are not typically recognized as ssRNA, but through intermittent replication products in the form of dsRNA. [5] [9] RIG-I is also able to detect non-self 5′-triphosphorylated dsRNA transcribed from AT-rich dsDNA by DNA-dependent RNA polymerase III (Pol III). [18] It is important to note, however, that the ligands of RIG-I are still being investigated and are controversial. Also notable, is that RIG-I can work together with MDA5 against viruses that RIG-I itself may not create a significant enough response. [5] [9] In addition, for many viruses, effective RIG-I-mediated antiviral responses are dependent on functionally active LGP2. [18] Cells are synthesizing multiple types of RNA at all times, so it is important that RIG-I is not going to bind to those RNAs. Native RNA from inside the cell contains an N1 2'O-Methyl self RNA marker that deters RIG-I from binding. [9] [10]

Type-1 Interferon Pathway

RIG-I is a signaling molecule and is usually in a condensed resting state until it is activated. Once RIG-I is bound to its PAMP, molecules such as PACT and zinc antiviral protein short isoform (ZAPs), help keep RIG-I in an activated state which then keeps the caspase activation and recruitment domains (CARDs) ready for binding. [5] The molecule will migrate to the mitochondrial antiviral signaling protein (MAVS) CARD domain and bind. [5] [9] RIG-I CARD interactions have their own regulatory system. Although RIG-I expresses a CARD at all times, it must be activated by the ligand before it will allow both CARDs to interact with the MAVS CARD. [9] This interaction will start the pathway to making proinflammatory cytokines and type-1 Interferon (IFN1;IFNα and IFNβ), which create an antiviral environment. [5] [9] Once the IFN1s leave the cell, they can bind to IFN1 receptors on the cell surface from which they came from, or other cells close by. [9] This will upregulate the production of more IFN1s, boosting an antiviral environment. [5] [9] IFN1 also activates the JAK-STAT pathway, leading to the production of IFN-stimulated genes (ISGs). [13]

In Cancer Cells

Usually, RIG-I recognizes foreign RNA. However, it can sometimes recognize "self" RNAs. RIG-I has been shown to enable breast cancer cells (BrCa) to resist treatments and grow because of an IFN response to noncoding RNA. In contrast, RIG-I in other types of cancer, such as acute myeloid leukemia and hepatocellular carcinoma, can act as a tumor suppressor. [10] If cancer causing viruses infect a cell, however, RIG-I can lead to cell death. Cell death can occur via apoptosis via the caspase-3 pathway, or through IFN-dependent T cells and natural killer cells. [19]

Identification and Naming

In 2000, RIG-I was named by researchers from the Shanghai Institute of Hematology who identified novel genes that respond to all-trans retinoic acid (ATRA) in leukemia cells. [20] RIG-I and the other genes were assigned the temporary name of RIG (retinoic acid–induced gene) in the format of RIG-A, RIG-B etc by the group, however they performed no additional characterization on RIG-I.

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.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNG protein is encoded by the IFNG gene.

<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">Innate immune system</span> Immunity strategy in living beings

The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<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.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

Type II cytokine receptors, also commonly known as class II cytokine receptors, are transmembrane proteins that are expressed on the surface of certain cells. They bind and respond to a select group of cytokines including interferon type I, interferon type II, interferon type III. and members of the interleukin-10 family These receptors are characterized by the lack of a WSXWS motif which differentiates them from type I cytokine receptors.

The type III interferon group is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. They were discovered in 2003. Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defense against viruses in the epithelium.

<span class="mw-page-title-main">IFNA2</span> Mammalian protein found in Homo sapiens

Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 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">MDA5</span> Mammalian protein found in Homo sapiens

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

<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">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

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: ENSG00000107201 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040296 – 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 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Kell AM, Gale M (May 2015). "RIG-I in RNA virus recognition". Virology. 479–480: 110–121. doi:10.1016/j.virol.2015.02.017. PMC   4424084 . PMID   25749629.
  6. 1 2 Solis M, Nakhaei P, Jalalirad M, Lacoste J, Douville R, Arguello M, et al. (February 2011). "RIG-I-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I". Journal of Virology. 85 (3): 1224–1236. doi:10.1128/JVI.01635-10. PMC   3020501 . PMID   21084468.
  7. ↑ Goubau D, Schlee M, Deddouche S, Pruijssers AJ, Zillinger T, Goldeck M, et al. (October 2014). "Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates". Nature. 514 (7522): 372–375. Bibcode:2014Natur.514..372G. doi:10.1038/nature13590. PMC   4201573 . PMID   25119032.
  8. ↑ Devarkar SC, Wang C, Miller MT, Ramanathan A, Jiang F, Khan AG, et al. (January 2016). "Structural basis for m7G recognition and 2'-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I". Proceedings of the National Academy of Sciences of the United States of America. 113 (3): 596–601. Bibcode:2016PNAS..113..596D. doi: 10.1073/pnas.1515152113 . PMC   4725518 . PMID   26733676.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 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.
  10. 1 2 3 4 Xu XX, Wan H, Nie L, Shao T, Xiang LX, Shao JZ (March 2018). "RIG-I: a multifunctional protein beyond a pattern recognition receptor". Protein & Cell. 9 (3): 246–253. doi:10.1007/s13238-017-0431-5. PMC   5829270 . PMID   28593618.
  11. ↑ Chiang JJ, Sparrer KM, van Gent M, Lässig C, Huang T, Osterrieder N, et al. (January 2018). "Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity". Nature Immunology. 19 (1): 53–62. doi:10.1038/s41590-017-0005-y. PMC   5815369 . PMID   29180807.
  12. ↑ Zhao Y, Ye X, Dunker W, Song Y, Karijolich J (November 2018). "RIG-I like receptor sensing of host RNAs facilitates the cell-intrinsic immune response to KSHV infection". Nature Communications. 9 (1): 4841. Bibcode:2018NatCo...9.4841Z. doi:10.1038/s41467-018-07314-7. PMC   6242832 . PMID   30451863.
  13. 1 2 Ivashkiv LB, Donlin LT (January 2014). "Regulation of type I interferon responses". Nature Reviews. Immunology. 14 (1): 36–49. doi:10.1038/nri3581. PMC   4084561 . PMID   24362405.
  14. ↑ Yu P, Miao Z, Li Y, Bansal R, Peppelenbosch MP, Pan Q (January 2021). "cGAS-STING effectively restricts murine norovirus infection but antagonizes the antiviral action of N-terminus of RIG-I in mouse macrophages". Gut Microbes. 13 (1): 1959839. doi:10.1080/19490976.2021.1959839. PMC   8344765 . PMID   34347572.
  15. ↑ "DDX58 DExD/H-box helicase 58 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-02-29.
  16. ↑ Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ (August 2011). "MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response". Cell. 146 (3): 448–461. doi:10.1016/j.cell.2011.06.041. PMC   3179916 . PMID   21782231.
  17. 1 2 Amarante-Mendes GP, Adjemian S, Branco LM, Zanetti LC, Weinlich R, Bortoluci KR (2018). "Pattern Recognition Receptors and the Host Cell Death Molecular Machinery". Frontiers in Immunology. 9: 2379. doi: 10.3389/fimmu.2018.02379 . PMC   6232773 . PMID   30459758.
  18. 1 2 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): 1512–1517. Bibcode:2010PNAS..107.1512S. doi: 10.1073/pnas.0912986107 . PMC   2824407 . PMID   20080593.
  19. ↑ Żeromski J, Kaczmarek M, Boruczkowski M, Kierepa A, Kowala-Piaskowska A, Mozer-Lisewska I (June 2019). "Significance and Role of Pattern Recognition Receptors in Malignancy". Archivum Immunologiae et Therapiae Experimentalis. 67 (3): 133–141. doi:10.1007/s00005-019-00540-x. PMC   6509067 . PMID   30976817.
  20. ↑ Liu TX, Zhang JW, Tao J, Zhang RB, Zhang QH, Zhao CJ, et al. (August 2000). "Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells". Blood. 96 (4): 1496–1504. doi: 10.1182/blood.V96.4.1496 . PMID   10942397.

Further reading

Note: RARRES3 (Gene ID: 5920) and DDX58 (Gene ID: 23586) share the RIG1/RIG-1 alias in common. RIG1 is a widely used alternative name for DExD/H-box helicase 58 (DDX58), which can be confused with the retinoic acid receptor responder 3 (RARRES3) gene, since they share the same alias. [22 Jan 2019]

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