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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes
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Cell Line
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Cytokines / metabolism
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Gene Expression
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Gene Knockout Techniques
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lipopolysaccharides / adverse effects
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Mutagenesis, Site-Directed
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NF-kappa B / drug effects
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NF-kappa B / metabolism
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Signal Transduction / drug effects
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T-Lymphocytes
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THP-1 Cells
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TNF Receptor-Associated Factor 2 / metabolism
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TNF Receptor-Associated Factor 6 / metabolism*
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Toll-Like Receptors / metabolism*
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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Cytokines
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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NF-kappa B
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 6
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Tifab protein, human
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Toll-Like Receptors
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RNF19A protein, human
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Ubiquitin-Protein Ligases