RIG-I-like receptor

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][2] 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.[3] 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.[3]

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.[4] As pattern recognition receptors, RLRs live in the cytosol of a cell, so that they can detect the presence of viral DNA or RNA.[5] 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.[4] 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.[4] LGP2, the remaining RLR, lacks the ability to induce signaling alone, but is necessary for effective RIG-I and MDA5-mediated antiviral responses.[6]

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.[6]

Each of the three RLRs contain a C-terminal DExD/H box helicase domain, which binds to double-stranded RNA, or dsRNA.[6] RIG-I and MDA5 each contain two N-terminal caspase activation and recruitment domains (CARD), which will initiate the anti-viral signaling pathway.[6]

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.[4] Instead, LGP2 modulates the other two RLRs through negative inhibition.[3] It is known that LGP2 binds a repressor domain on the RIG-I C-terminal region to suppress RIG-1 signaling and down-regulate the viral response.[7][6]

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.[5] RIG-I, specifically, detects a 5' triphosphate addition on single-stranded RNA, as a means of differentiating from self-RNA.[3]

RIG-I and MDA5 both contain two CARD-domains for induction of an intracellular response, and as such have a very similar signaling pathway.[7] 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.[3] These signals for viral inhibition cannot be transmitted without a functional CARD domain.[3]

During viral infection, cleavage of self-RNA creates a ligand that 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).[7]

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.[5] 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-κB pathway.[5] The NF-κB pathway releases cytokines, antimicrobials, and chemokines, which are all part of the pro-inflammatory innate immune response.[5]

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.[3]

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,[7] 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.[3] RIG-I has viral ligand specificity for paramyxoviruses, vesicular stomatitis virus, Japanese encephalitis virus, and influenza virus.[7][3] MDA5 is specific to Picornaviruses, including encephalomyocarditis virus, Mengo virus, and Theiler's virus, and is involved in recognition of ployIC, an immunostimulant.[7][3] 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.[3]

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.[7][4]

See also

References

  1. ↑ Mahla RS, Reddy MC, Prasad DV, Kumar H (September 2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Frontiers in Immunology. 4: 248. doi:10.3389/fimmu.2013.00248. PMC 3759294. PMID 24032031.
  2. ↑ Stefan Offermanns; Walter Rosenthal. Encyclopedia of Molecular Pharmacology, Volume 1. Springer. Retrieved 30 August 2011. The other two families of PRRs, the NOD-like receptors (NLRs) and the RIG-like helicases (RLHs) are soluble receptors present in the cytosol and act as sensors to detect a variety of viral and bacterial products.
  3. 1 2 3 4 5 6 7 8 9 10 11 Yoneyama, Mitsutoshi; Fujita, Takashi (2007-05-25). "Function of RIG-I-like receptors in antiviral innate immunity". The Journal of Biological Chemistry. 282 (21): 15315–15318. doi:10.1074/jbc.R700007200. ISSN 0021-9258. PMID 17395582.
  4. 1 2 3 4 5 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.
  5. 1 2 3 4 5 A., Owen, Judith (2013). Kuby immunology. Punt, Jenni., Stranford, Sharon A., Jones, Patricia P., Kuby, Janis. (7th ed.). New York: W.H. Freeman. ISBN 1464119910. OCLC 820117219.
  6. 1 2 3 4 5 Thompson, Alex J. V.; Locarnini, Stephen A. (August 2007). "Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response". Immunology and Cell Biology. 85 (6): 435–445. doi:10.1038/sj.icb.7100100. ISSN 0818-9641. PMID 17667934.
  7. 1 2 3 4 5 6 7 Kawai, Taro; Akira, Shizuo (2008-11-01). "Toll-like Receptor and RIG-1-like Receptor Signaling". Annals of the New York Academy of Sciences. 1143 (1): 1–20. doi:10.1196/annals.1443.020. ISSN 1749-6632.
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