RIG-I-like receptor
RIG-I-like receptors (retinoic acid-inducible gene-I-like receptors, RLRs) are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system.[1][2] RIG-I (retinoic-acid inducible gene or DDX58) is the best characterized receptor within the RIG-I like receptor (RLR) family. Together with MDA5 (melanoma differentiation-associated 5) and LGP2 (laboratory of genetics and physiology 2), 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.
RLR ligands
The RIG-I receptor prefers to bind short (<2000 bp) single- or double-stranded
Structural features
The RLR receptors are members of the
Activation of signaling
In uninfected cells that are absent of viral RNA RIG-I exists in an inactive conformation in which the CARD domains are masked due to their interaction with the CTD.
RIG-I antiviral signaling
In the activated state the exposed RIG-I CARD domains interact with the CARD domains of
Regulation
As prolonged IFN production is linked to human disease RLR signaling must be tightly regulated. One of various ways that this is achieved is by post-translationally modifying, or tagging, host RLR signaling proteins with phosphate (known as phosphorylation) or ubiquitin (known as ubiquitination). These tags can also be removed, which adds an additional regulatory layer to RLR signaling. These post-translational modifications, and their removal, are prevalent in RLR signaling and even regulate the RIG-I receptor itself. Most famously the RIG-I CARD domain is phosphorylated by protein kinase C-α (PKC-α) and PKC-β in the resting state to negatively regulate signaling.[24][25][26] Upon viral infection RIG-I is dephosphorylated by PP1α and PP1γ,[27] permitting the ubiquitination of the RIG-I CARD domain by the E3 ligase TRIM25 to activate the RLR-mediated antiviral immune response.[28] Given post-translational modifications are so pertinent to the activation of RLR signaling, it is not surprising that they are directly, or indirectly, targeted by viruses such as influenza A[29] and measles,[30] respectively, to suppress signaling.
Viral hijacking of RLR signaling
Viruses have evolved ways to subvert RLR signaling to enhance their survival. For example, influenza A virus and West Nile virus (WNV) use their NS1 (nonstructural protein 1) proteins to block RIG-I ubiquitination by TRIM25, or cause RIG-I degradation, respectively, which in turn inhibits IFN production.[29][31] This outcome is also achieved by the hepatitis C (HCV) NS3/4A protein by cleaving a part of MAVS,[32] and the foot-and-mouth disease virus (FMDV) leader protease (Lpro) which cleaves LGP2.[33] Likewise, dengue virus (DENV) uses its NS2B3, NS2A and NS4B proteins to bind IKKε and prevent IRF3 phosphorylation[34][35] and its NS4A protein, as per the zika virus, to bind MAVS to block RLR receptor binding.[36][37] Another prominent example is that of the paramyxovirus V proteins, which directly bind various RLR or downstream signaling proteins including MDA5, LGP2, and STAT,[38][39][40] or proteins such as PP1α and PP1γ[30] that negatively regulate RLR signaling.
See also
References
This article was adapted from the following source under a CC BY 4.0 license (2019) (reviewer reports):
Natalie Borg (2019). "RIG-I like receptors" (PDF). WikiJournal of Science. 2 (1): 1. {{cite journal}}
: CS1 maint: unflagged free DOI (link
- PMID 24032031.
- ISBN 9783540389163. 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.
- PMID 18591409.
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- PMID 20805493.
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- S2CID 22436759.
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- S2CID 2270879.
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- S2CID 4404114.
- ^ PMID 19454348.
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External links
- PTHR14074: Helicase with Death Domain-Related (filter for human)