RNA sensor LGP2 inhibits TRAF ubiquitin ligase to negatively regulate innate immune signaling

Jean Patrick Parisien, Jessica J. Lenoir, Roli Mandhana, Kenny R. Rodriguez, Kenin Qian, Annie M. Bruns, Curt M. Horvath*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The production of type I interferon (IFN) is essential for cellular barrier functions and innate and adaptive antiviral immunity. In response to virus infections, RNA receptors RIG-I and MDA5 stimulate a mitochondria-localized signaling apparatus that uses TRAF family ubiquitin ligase proteins to activate master transcription regulators IRF3 and NFκB, driving IFN and antiviral target gene expression. Data indicate that a third RNA receptor, LGP2, acts as a negative regulator of antiviral signaling by interfering with TRAF family proteins. Disruption of LGP2 expression in cells results in earlier and overactive transcriptional responses to virus or dsRNA. LGP2 associates with the C-terminus of TRAF2, TRAF3, TRAF5, and TRAF6 and interferes with TRAF ubiquitin ligase activity. TRAF interference is independent of LGP2 ATP hydrolysis, RNA binding, or its C-terminal domain, and LGP2 can regulate TRAF-mediated signaling pathways in trans, including IL-1β, TNFα, and cGAMP. These findings provide a unique mechanism for LGP2 negative regulation through TRAF suppression and extend the potential impact of LGP2 negative regulation beyond the IFN antiviral response.

Original languageEnglish (US)
Article numbere45176
JournalEMBO Reports
Volume19
Issue number6
DOIs
StatePublished - Jun 2018

Keywords

  • LGP2
  • RIG-I-like receptors
  • TRAF
  • innate immunity
  • interferon

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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