Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the MAVS-TRAF3 complex

Cell Host Microbe. 2012 Aug 16;12(2):211-22. doi: 10.1016/j.chom.2012.06.009.

Abstract

The RIG-I/Mda5 sensors recognize viral intracellular RNA and trigger host antiviral responses. RIG-I signals through the adaptor protein MAVS, which engages various TRAF family members and results in type I interferon (IFNs) and proinflammatory cytokine production via activation of IRFs and NF-κB, respectively. Both the IRF and NF-κB pathways also require the adaptor protein NEMO. We determined that the RIG-I pathway is differentially regulated by the linear ubiquitin assembly complex (LUBAC), which consists of the E3 ligases HOIL-1L, HOIP, and the accessory protein SHARPIN. LUBAC downregulated virus-mediated IFN induction by targeting NEMO for linear ubiquitination. Linear ubiquitinated NEMO associated with TRAF3 and disrupted the MAVS-TRAF3 complex, which inhibited IFN activation while stimulating NF-κB-dependent signaling. In SHARPIN-deficient MEFs, vesicular stomatitis virus replication was decreased due to increased IFN production. Linear ubiquitination thus switches NEMO from a positive to a negative regulator of RIG-I signaling, resulting in an attenuated IFN response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line
  • Down-Regulation
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism*
  • Interferons / immunology*
  • Mice
  • Mice, Knockout
  • Protein Binding
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / metabolism*
  • Ubiquitination
  • Vesicular Stomatitis / genetics
  • Vesicular Stomatitis / immunology
  • Vesicular Stomatitis / metabolism*
  • Vesicular Stomatitis / virology
  • Vesicular stomatitis Indiana virus / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • IKBKG protein, human
  • TNF Receptor-Associated Factor 3
  • VISA protein, human
  • Interferons
  • I-kappa B Kinase