RNA Helicase LGP2 Negatively Regulates RIG-I Signaling by Preventing TRIM25-Mediated Caspase Activation and Recruitment Domain Ubiquitination

Kendra M. Quicke, Kristin Y. Kim, Curt M. Horvath, Mehul S. Suthar*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)669-683
Number of pages15
JournalJournal of Interferon and Cytokine Research
Volume39
Issue number11
DOIs
StatePublished - Nov 2019

Keywords

  • LGP2
  • RIG-I-like receptors
  • TRIM25
  • ubiquitination

ASJC Scopus subject areas

  • Immunology
  • Cell Biology
  • Virology

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