The Thermodynamic Basis for Viral RNA Detection by the RIG-I Innate Immune Sensor

By Adriana Vela, O. Fedorova, S. Ding, Anna Marie Pyle. 2012

64 citations recorded by the source corpus.

Background: RIG-I is an essential innate immune receptor that detects viral RNAs in infected cells. Results: RIG-I uses distinct subdomains to recognize specific characteristics of viral RNAs. Conclusion: The 5′-triphosphate is critical for high affinity RIG-I/RNA interaction. Significance: Characterizing the RIG-I/RNA interface is essential for understanding early stages of immune response against RNA viruses. RIG-I is a cytoplasmic surveillance protein that contributes to the earliest stages of the vertebrate innate immune response. The protein specifically recognizes 5′-triphosphorylated RNA structures that are released into the cell by viruses, such as influenza and hepatitis C. To understand the energetic basis for viral RNA recognition by RIG-I, we studied the binding of RIG-I domain variants to a family of dsRNA ligands. Thermodynamic analysis revealed that the isolated RIG-I domains each make important contributions to affinity and that they interact using different strategies. Covalent linkage between the domains enhances RNA ligand specificity while reducing overall binding affinity, thereby providing a mechanism for discriminating virus from host RNA.

Subfields: Epidemiology, Immunology

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Citations in the corpus

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, neutral): “Indeed, direct studies of RIG-I binding to internal duplexes has shown that these complexes are very weak (4–5 orders of magnitude weaker than binding to the terminus of RNA duplexes (Devarkar et al., 2018; Rawling et al., 2015; Ren et al., 2019; Vela et al., 2012).”
An evolving arsenal: viral RNA detection by RIG-I-like receptors (2014, background): “To facilitate the detection of a broad range of non-self RNA targets, each RLR contains a similar but divergent C-terminal domain (CTD) that mediates RLR-specific interactions between bound nucleic acids or neighboring protein partners [13,14].”
Establishing the role of ATP for the function of the RIG-I innate immune sensor (2015, background): “By contrast, the CTD of RIG-I molecules bound at internal sites is effectively disengaged, and it is likely that all interactions between RIG-I and internal sites occur exclusively through contacts involving the helicase domain (Vela et al., 2012).”
Cytosolic Sensing of Viruses (2013, background): “Indeed, thermodynamic analysis revealed that full-length RIG-I recognizes RNA with a 50 PPP with an affinity that is 126-fold higher than that for RNA with a 50 hydroxyl group (Vela et al., 2012).”
A structure-based model of RIG-I activation. (2012, background): “Finally, in a short space of time in 2011, four groups independently reported high-resolution structures of RIG-I and RIG-I RNA complexes that extend previous structural studies that revealed how the CTD preferentially bound 59pppbpRNA (Lu et al. 2010; Wang et al. 2010).”
The RIG-I ATPase core has evolved a functional requirement for allosteric stabilization by the Pincer domain (2014, methodology): “For WT RIG-I, we determined a mean Kd, 5′OH10L of 25 ± 4 nM, which is in good agreement with previously published data on similar ligands (50).”
Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5 (2015, unknown): “Upon viral infection, RIG-I CTD selectively traps non-self dsRNA ectopically present in the cytosol with high affinity (nM range [31, 32, 60]) (Fig.”
Defining the functional determinants for RNA surveillance by RIG-I (2013, unknown): “Furthermore, the RIG-I helicase domain exhibits weak, micromolar affinity for blunt-ended duplex RNA that is terminated either by a 50triphosphate or 50hydroxyl [19,21], suggesting that internal duplex stem binding has a lesser role in RIG-I stimulation.”
RNA binding activates RIG-I by releasing an autorepressed signaling domain (2019, methodology): “MATERIALS AND METHODS Cloning and protein construct creation Full-length human RIG-I was previously cloned into a pET SUMO expression vector (19).”
Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding (2016, background): “disengaged and interactions with the RNA occur exclusively through contacts involving the helicase domain (13).”