NLRP11 attenuates Toll-like receptor signalling by targeting TRAF6 for degradation via the ubiquitin ligase RNF19A

Nat Commun. 2017 Dec 7;8(1):1977. doi: 10.1038/s41467-017-02073-3.

Abstract

The adaptor protein TRAF6 has a central function in Toll-like receptor (TLR) signalling, yet the molecular mechanisms controlling its activity and stability are unclear. Here we show that NLRP11, a primate specific gene, inhibits TLR signalling by targeting TRAF6 for degradation. NLRP11 recruits the ubiquitin ligase RNF19A to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, thereby leading to the degradation of TRAF6. Furthermore, deficiency in either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6, which promotes activation of NF-κB and MAPK signalling and increases the production of proinflammatory cytokines. Therefore, our findings identify NLRP11 as a conserved negative regulator of TLR signalling in primate cells and reveal a mechanism by which the NLRP11-RNF19A axis targets TRAF6 for degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes
  • Cell Line
  • Cytokines / metabolism
  • Gene Expression
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipopolysaccharides / adverse effects
  • Mutagenesis, Site-Directed
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocytes
  • THP-1 Cells
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Toll-Like Receptors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6
  • Tifab protein, human
  • Toll-Like Receptors
  • RNF19A protein, human
  • Ubiquitin-Protein Ligases