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.
Highlights
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
We found that monocytes showed the highest expression levels of NLRP11, suggesting that NLRP11 may play a significant role in monocytes (Fig. 1b, Supplementary Fig. 1a)
We found that NLRP11 failed to inhibit NF-κB activation induced by the 3KR TRAF6 mutant, whereas NF-κB activation induced by WT TRAF6 or by other TRAF6 mutants was strongly inhibited by NLRP11 (Fig. 6g)
Summary
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. We show that NLRP11, a primate specific gene, inhibits TLR signalling by targeting TRAF6 for degradation. 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. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China. 6 Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Recognition of microbial pathogens is crucial for the initiation of innate immune responses and is mediated by germline-encoded pattern-recognition receptors (PRR) that detect conserved features of invading microorganisms, termed pathogen associated molecular patterns (PAMP)[1,2,3,4,5]. Whether additional regulators are responsible for K48-linked ubiquitination of TRAF6 for regulation of its stability is unknown
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