Establishing the role of ATP for the function of the RIG-I innate immune sensor

By David C. Rawling, Megan E. Fitzgerald, Anna Marie Pyle. 2015

58 citations recorded by the source corpus.

Retinoic acid-inducible gene I (RIG-I) initiates a rapid innate immune response upon detection and binding to viral ribonucleic acid (RNA). This signal activation occurs only when pathogenic RNA is identified, despite the ability of RIG-I to bind endogenous RNA while surveying the cytoplasm. Here we show that ATP binding and hydrolysis by RIG-I play a key role in the identification of viral targets and the activation of signaling. Using biochemical and cell-based assays together with mutagenesis, we show that ATP binding, and not hydrolysis, is required for RIG-I signaling on viral RNA. However, we show that ATP hydrolysis does provide an important function by recycling RIG-I and promoting its dissociation from non-pathogenic RNA. This activity provides a valuable proof-reading mechanism that enhances specificity and prevents an antiviral response upon encounter with host RNA molecules. DOI: http://dx.doi.org/10.7554/eLife.09391.001

Subfields: Immunology, Molecular Biology

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Citations in the corpus

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, methodology): “HF complexes form a reduced network of interactions with dsRNA, which is consistent with their fast off rates (Devarkar et al., 2018;Rawling et al., 2015) and lowbinding affinity (Ren et al., 2019; Vela et al., 2012).”
A minimal RNA ligand for potent RIG-I activation in living mice (2017, result): “Taken together, these findings confirm previous work demonstrating the potency of SLRs in cell culture (10, 37, 38), and benchmark SLR potency relative to other putative RIG-I ligands.”
RIG-I uses an ATPase-powered translocation-throttling mechanism for kinetic proofreading of RNAs and oligomerization (2018, methodology): “One model suggested that ATP binding provides a proofreading function by preferentially dissociating RIG-I from nonPAMP RNAs (Rawling et al., 2015).”
RNA binding activates RIG-I by releasing an autorepressed signaling domain (2019, background): “For example, RNAs that bind RIG-I or stimulate ATP hydrolysis do not always signal in cells (18, 20).”
Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants (2018, methodology): “In the absence of any RNA ligand, both wild type RIG-I and ATP-hydrolysis-deficient RIG-I E373Q show comparable affinities for MANT-ATP and MANT-ATPgS in the low mM range (Table 1).”