Spatiotemporal Regulation of RIG-I-Like Receptor Signaling by Endosomes 2305200

Abstract Introduction RIG-I-like receptors are cytosolic viral RNA sensors that are critical for type I interferon (IFN)-driven antiviral defense against RNA virus infections. RIG-I has been shown to survey viral RNA in subcellular compartments, including stress granules, mitochondria-associated membranes, microsomes, and the nucleus, after virus invasion. Our recent work revealed a novel RIG-I action mode in which RIG-I is recruited onto endosomes, the “gateway” of virus entry into a host cell, to detect viral RNA upon viral breaching the endosomes. Endosomes serve as signaling platforms for the ubiquitination and activation of RIG-I. To better understand this novel RIG-I action mode, we further explored the spatiotemporal regulation of RIG-I signaling by endosomes, as well as the potential interplay between MDA5 and endosomes. Methods Biochemical and microscopic analyses are employed to investigate the interaction between RLRs and endosomes. Genetic approaches are employed to investigate the role of the endosomal adaptor TAPE in antiviral defense in vivo. Results Our data suggest that endosomes act as signaling platforms for MDA5 ubiquitination and activation. Conclusion These novel action modes of RIG-I-like receptors reveal the host’s early engagement with viruses to trigger antiviral defense. Funding Source Taiwan National Science and Technology Council Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)