RNA binding activates RIG-I by releasing an autorepressed signaling domain

By T. Dickey, B. Song, Anna Marie Pyle. 2019

18 citations recorded by the source corpus.

Direct monitoring of RIG-I activation by FRET reveals reversible activation by RNA alone. The retinoic acid–inducible gene I (RIG-I) innate immune receptor is an important immunotherapeutic target, but we lack approaches for monitoring the physical basis for its activation in vitro. This gap in our understanding has led to confusion about mechanisms of RIG-I activation and difficulty discovering agonists and antagonists. We therefore created a novel fluorescence resonance energy transfer–based method for measuring RIG-I activation in vitro using dual site-specific fluorescent labeling of the protein. This approach enables us to measure the conformational change that releases the signaling domain during the first step of RIG-I activation, making it possible to understand the role of stimulatory ligands. We have found that RNA alone is sufficient to eject the signaling domain, ejection is reversible, and adenosine triphosphate plays but a minor role in this process. These findings help explain RIG-I dysfunction in autoimmune disease, and they inform the design of therapeutics targeting RIG-I.

Subfields: Immunology, Oncology

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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): “The stem loop RNA (p3SLR30) was in-vitro transcribed, purified and evaluated as described previously (Dickey et al., 2019; Rawling et al., 2015).”