RNA binding activates RIG-I by releasing an autorepressed signaling domain
Year: 2019
Type: article
Abstract: 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.
Source: Science Advances
Authors: T. H. Dickey, B. Song, A. M. Pyle
Institutions: Yale University, Howard Hughes Medical Institute
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funder: Howard Hughes Medical Institute
OpenAlex ID: W2978339175