User:Immcarle76/sandbox

RIG-I-like receptors (existing article)

RIG-I-like receptors, abbreviated RLRs, are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system.There are three RLRs: RIG-I, MDA5, and LGP2 that act as sensors of viral replication within the cytoplasm of human cells; though each of these three receptors is located in tissues throughout the body, RLRs are especially active in the innate immune defense of epithelial cells, myeloid cells, and cells of the central nervous system. RLRs detect viral replication through direct interaction with dsRNA, which is produced by RNA viruses to form their genome (dsRNA viruses) or as a part of their replication cycle. RIG-1, specifically, is able to identify this viral, double-stranded RNA in the cytoplasm due to the presence of a 5'-triphosphate non-self marker.Two of the RLRs, RIG-I and MDA5, possess the ability to induce a cellular response (via CARD domains) upon recognition of viral dsRNA. LGP2, the remaining RLR, lacks the ability to induce signaling alone (due to the absence of CARD domains), but has been found to be necessary for effective RIG-I and MDA5-mediated antiviral responses. Recognition of viruses by RLRs typically leads to the production of type I interferons through the activation of a complex signaling network.

Article Evaluation

The article is short and full of technical terms and scientific information. The tone seems quite neutral, and the information fact-based. The article definitely needs to be expanded to include accessible and comprehensive information on the topic.

The article does not provide me enough information to understand this topic, meaning that before I begin the editing project I'll have to do some research to gain a most basic understanding of my focus.

There are currently four references cited in the article, all of which appear to be credible sources with functional links. However, the information could definitely include more citations. While the sources don't seem biased, the information in the article is lacking in the sense that it is a bit too intellectual and brief. More information will require more credible sources.

The article is currently rated as Stub-class (low-quality article with little meaningful content) on two WikiProject pages: Medicine and Molecular and Cell Biology.

There is one asked and answered question about the relationship between RIG-I-like receptors and RNA helicase on the article's Talk page, dating from 2016.

Expanded Outline

I plan to expand this article, to turn it into a comprehensive resource on RLRs. My research and writing will have the following structure:

• Overview
  • modify and incorporate existing article text: RIG-I-like receptors, abbreviated RLRs, are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system.^[1]There are three RLRs: RIG-I, MDA5, and LGP2 that act as sensors of viral replication within the cytoplasm of human cells; though each of these three receptors is located in tissues throughout the body, RLRs are especially active in the innate immune defense of epithelial cells, myeloid cells, and cells of the central nervous system.^[2] RLRs detect viral replication through direct interaction with dsRNA, which is produced by RNA viruses to form their genome (dsRNA viruses) or as a part of their replication cycle. RIG-1, specifically, is able to identify this viral, double-stranded RNA in the cytoplasm due to the presence of a 5'-triphosphate non-self marker.^[3][4]Two of the RLRs, RIG-I and MDA5, possess the ability to induce a cellular response (via CARD domains) upon recognition of viral dsRNA. LGP2, the remaining RLR, lacks the ability to induce signaling alone (due to the absence of CARD domains), but has been found to be necessary for effective RIG-I and MDA5-mediated antiviral responses.^[5] Recognition of viruses by RLRs typically leads to the production of type I interferons through the activation of a complex signaling network.^[6][7]
  • Retinoic acid-inducible gene-I-like receptors (RLRs)
    • Three DExD/H box helicases, termed retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated antigen 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2)
    • RIG-1 discovery, analysis preceded the other two
  • serve as PRR for viral infection, and live in cytosol so that they can recognize viral RNA
  • relationship to RIG-I-like RNA helicases
    • importance in detection of viruses for innate immune response
• Function
  • detection of viruses for innate immune response, which will lead to adaptive immune response
• Signaling pathway
  • Structure
    • Details on the differences between the 3 RLRs: RIG-I, MDA5, LGP2   
  • Activation (pathogen sensing)
    • recognition by features of viral RNA:
      • double-stranded regions
      • specific sequences
      •  5” triphosphate modification (recognized by RIG-I)
    • RIG-1 mechanism of binding:
      • helicase activity unwinds dsRNA with a 3’- triphosphate
      • blunt ends and 5’ overhang bind with RIG-1 very stably
      • cleavage of self-RNA with viral infection creates ligand to bind to RIG-1 and MDA-5 to amplify IFN 1 responses
    • RIG-I is activated by dsRNA 
    • binding of dsRNA or ssRNA to helicase releases CARD domain (by conformational change) to initiate signaling
      • LGP2 lacks CARD, and so is not capable of transmitting the same positive signal
        • is likely a negative inhibitor
  • Response
    • CARD domain cellular response in RIG-I and MDA-5
    • LGP2 does not induce the same signaling pathway, but may modulate the other two RLRs
    • RIG-I contains two repeats of the caspase recruitment domain (CARD)-like motif at its N terminus
      • RIG-1 undergoes a conformational change that allows for CARD-CARD binding to downstream adaptor molecule, MAVS (mitochondrial anti-viral signaling protein) in mitochondrial membrane
        • MAVS activates further proteins in a full signaling cascade (TRADD, TRAF3, R1P1 to NEMO/IKKs to IKK complexes to IRFs 3, 7, NFKB pathway)
        • NFKB pathway leads to secretion of pro-inflammatory cytokines, anticmicrobials, chemokines, etc.   
        • signaling domain to interact with IPS-1 (also called MAVS)
          • IPS-1 activates NF-KB and IRF-3,7

• • • • • MDA-5 sends CARD here too
          • structural similarity
          • different cytokine genes ultimately activated, though
      • without functional CARD domain, cannot transmit the signal for viral inhibition
  • Relationship to the broader innate immune system
    • inflammatory response
    • RIG-1 and MDA5 sense different viruses (deficiency of one leads to lack of production of cytokines when faced with a certain virus)
      • role of innate system to adaptive response
        • viral proteins have evolved to counteract RLR signaling
          • lots of examples of these
    • MDA5 and RIG-I have differing viral ligand specificity
      • lead to production of type 1 IFN and inflammatory cytokines

Article Draft

RIG-I-like receptors (retinoic acid-inducible gene-I-like receptors, or RLRs,) are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system.^[1] There are three RLRs - RIG-I, MDA5, and LGP2 - that act as sensors of viral replication within the cytoplasm of human cells, and each has a DExD/H box helicase structure. The discovery and analysis of RIG-I preceded the discovery of MDA5 and LGP2, meaning that much more is known about RIG-I than the other two RLRs.

Though each of these three receptors is located in tissues throughout the body, RLRs are especially active in the innate immune defense of epithelial cells, myeloid cells, and CNS cells. As pattern recognition receptors, RLRs live in the cytosol of a cell, so that they can detect the presence of viral DNA or RNA. Upon detection of a viral infection, two of the RLRs, RIG-I and MDA5, possess the ability to activate a complex signaling network that leads to the production of pro-inflammatory molecules.^[6][7] RIG-I and MDA5 recognize distinct viruses but both produce the antiviral immune changes that initiate an innate response and regulate the subsequent adaptive response. LGP2, the remaining RLR, lacks the ability to induce signaling alone, but is necessary for effective RIG-I and MDA5-mediated antiviral responses.^[5]

Function and structure

RIG-I and MDA5

As opposed to other receptors, such as toll-like receptors (TLRs) which recognize extracellular viruses, RLRs serve to recognize viruses that have already entered into the cytoplasm of a cell.

Each of the three RLRs contain a a C-terminal DExD/H box helicase domain, which binds to double-stranded RNA, or dsRNA. RIG-I and MDA5 each contain two N-terminal caspase activation and recruitment domains (CARD), which will initiate the anti-viral signaling pathway.

LGP2

LGP2 does not have CARD-domains and therefore does not positively induce the same signaling pathway as RIG-I and MDA5. LGP2 also does not participate in viral detection. Instead, LPG2 modulates the other two RLRs through negative inhibition. It is known that LPG2 binds a repressor domain on the RIG-I C-terminal region to suppress RIG-1 signaling and down-regulate the viral response.

Signaling pathway of RIG-I and MDA5

Activation

Because RLRs are pattern recognition receptors, there are certain features of viral dsRNA or ssRNA (single-stranded RNA) that RLRs are equipped to detect. These include double-stranded regions, specific nucleotide sequences, and 5' triphosphate modifications. RIG-I, specifically, detects a 5' triphosphate addition on single-stranded RNA, as a means of differentiating from self-RNA.

RIG-I and MDA5 both contain two CARD-domains for induction of an intracellular response, and as such have a very similar signaling pathway. The binding of the RIG-1 or MDA5 helicase to a ssRNA or dsRNA induces a conformational change in the proteins, which releases the CARD domain to initiate signaling. These signals for viral inhibition cannot be transmitted without a functional CARD domain.

During viral infection, cleavage of self-RNA creates a that ligand will also bind to RIG-I and MDA5 to further amplify the anti-viral signaling pathway and increase the intracellular cytokine response (specifically type I IFNs).

Response

Upon activation of RIG-I, the conformational change in the protein allows for CARD-CARD binding to MAVS (mitochondrial antiviral signaling protein, also called IPS-1) a downstream adaptor molecule found in the mitochondrial membrane. MAVS furthers the signaling cascade; TRADD, TRAF3, and RIP1 activate NEMO/IKKs, which activate IKK complexes, to induce IRF-3, IRF-7, and the NF-kB pathway. The NF-kB pathway releases cytokines, antimicrobials, and chemokines, which are all part of the pro-inflammatory innate immune response.

MDA-5 activation also promotes CARD-CARD binding to MAVS, inducing the same signaling cascade. As such, the pathways for the two receptors are structurally similar, but will ultimately result in production of different cytokines.

RLRs and the immune system

Studies of RIG-I and MDA5 knock-out mice have shown that though both RLRs lead to production of type I IFNs and inflammatory cytokines, each RLR recognizes separate viral patterns; a deficiency of one type of RLR leads to a lack of cytokine production in response to a particular type of virus. RIG-I has viral ligand specificity for paramyxoviruses, vesicular stomatitis virus, Japanese encephalitis virus, and influenza virus. MDA5 is specific to Picornaviruses, including encephalomyocarditis virus, Mengo virus, and Theiler’s virus, and is involved in recognition of ployIC, an immunostimulant. Viral proteins have also evolved to counteract and avoid RLR signaling and the ensuing inflammatory response, such as paramyxoviruses, which have V proteins that block RLR signaling through interaction with MDA5.

RLRs work alongside another type of pattern recognition receptor, toll-like receptors (TLRs.) Both types of receptor are used for sensing viral infection, initiating the innate immune response, and mediating the adaptive immune response.

Sources

Kawai, T., & Akira, S. (2008). The year in immunology 2008 / (Vol. 1143, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES). Malden, Mass. :: Wiley-Blackwell.

Loo YM, Gale M (May 2011). "Immune signaling by RIG-I-like receptors". Immunity. 34 (5): 680–92. doi:10.1016/j.immuni.2011.05.003. PMC 3177755 . PMID 21616437. https://search.proquest.com/docview/1644732877?accountid=9892

Owen, J., Punt, J., Stranford, S., Jones, P., & Kuby, J. (2013). Kuby immunology (Seventh ed.). New York: W.H. Freeman and Company.

Thompson AJ, Locarnini SA (August 2007). "Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response". Immunology and Cell Biology. 85 (6): 435–45. doi:10.1038/sj.icb.7100100. PMID 17667934.https://www.researchgate.net/profile/Alex_Thompson2/publication/6171260_Toll-like_receptors_RIG-I-like_RNA_helicases_and_the_antiviral_innate_immune_response/links/0f3175350782d0752c000000.pdf

Yoneyama M, Fujita T (May 2007). "Function of RIG-I-like receptors in antiviral innate immunity". The Journal of Biological Chemistry. 282 (21): 15315–8. doi:10.1074/jbc.R700007200. PMID 17395582. http://www.jbc.org/content/282/21/15315