@article{45780845c9584769af10fa8e01c617c2,
title = "RNA Helicase LGP2 Negatively Regulates RIG-I Signaling by Preventing TRIM25-Mediated Caspase Activation and Recruitment Domain Ubiquitination",
abstract = "The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are a family of cytosolic pattern recognition receptors that play a critical role in binding viral RNA and triggering antiviral immune responses. The RLR LGP2 (or DHX58) is a known regulator of the RIG-I signaling pathway; however, the underlying mechanism by which LGP2 regulates RIG-I signaling is poorly understood. To better understand the effects of LGP2 on RIG-I-specific signaling and myeloid cell responses, we probed RIG-I signaling using a highly specific RIG-I agonist to compare transcriptional profiles between WT and Dhx58-/- C57BL\6 bone marrow-derived dendritic cells. Dhx58-/- cells exhibited a marked increase in the magnitude and kinetics of type I interferon (IFN) induction and a broader antiviral response as early as 1 h post-treatment. We determined that LGP2 inhibited RIG-I-mediated IFN-β, IRF-3, and NF-κB promoter activities, indicating a function upstream of the RLR adaptor protein mitochondrial antiviral signaling. Mutational analysis of LGP2 revealed that RNA binding, ATP hydrolysis, and the C-terminal domain fragment were dispensable for inhibiting RIG-I signaling. Using mass spectrometry, we discovered that LGP2 interacted with the E3 ubiquitin ligase TRIM25. Finally, we determined that LGP2 inhibited the TRIM25-mediated K63-specific ubiquitination of the RIG-I N-terminus required for signaling activation.",
keywords = "LGP2, RIG-I-like receptors, TRIM25, ubiquitination",
author = "Quicke, {Kendra M.} and Kim, {Kristin Y.} and Horvath, {Curt M.} and Suthar, {Mehul S.}",
note = "Funding Information: This work was funded, in part, by National Institutes of Health grants U19AI083019 (M.S.S), R56AI110516 (M.S.S), R21AI113485 (M.S.S.), U01AI131566 (M.S.S.), and R01GM111652 (C.M.H.) and Children{\textquoteright}s Health care of Atlanta, Emory Vaccine Center, Junior Faculty Focused award and The Georgia Research Alliance (M.S.S), and P510D11132 to Yerkes National Primate Research Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Funding Information: The authors acknowledge the expertise of the Yerkes Genomics Core in performing mRNA-sequencing, the Emory Integrated Proteomics Core in performing mass spectrometry, and the Pediatrics Department Flow Core for the upkeep and use of their flow cytometry and multiplex bead assay machines. The authors thank the EVC Flow Cytometry Core, which is supported, in part, by the National Institutes of Health grant P30A050509. Funding Information: The authors acknowledge the expertise of the Yerkes Genomics Core in performing mRNA-sequencing, the Emory Integrated Proteomics Core in performing mass spectrometry, and the Pediatrics Department Flow Core for the upkeep and use of their flow cytometry and multiplex bead assay machines. The authors thank the EVC Flow Cytometry Core, which is supported, in part, by the National Institutes of Health grant P30A050509. This work was funded, in part, by National Institutes of Health grants U19AI083019 (M.S.S), R56AI110516 (M.S.S), R21AI113485 (M.S.S.), U01AI131566 (M.S.S.), and R01GM111652 (C.M.H.) and Children s Health care of Atlanta, Emory Vaccine Center, Junior Faculty Focused award and The Georgia Research Alliance (M.S.S), and P510D11132 to Yerkes National Primate Research Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Publisher Copyright: {\textcopyright} Copyright 2019, Mary Ann Liebert, Inc., publishers 2019.",
year = "2019",
month = nov,
doi = "10.1089/jir.2019.0059",
language = "English (US)",
volume = "39",
pages = "669--683",
journal = "Journal of Interferon and Cytokine Research",
issn = "1079-9907",
publisher = "Mary Ann Liebert Inc.",
number = "11",
}