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

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.

Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN)

“…Since Lys48-linked (K48-linked) poly-ubiquitination on a target protein results in proteasome degradation [22,23], we determined whether UCHL1 mediates K48-linked poly-ubiquitination on CTTN. As expected, mutation of the Lys48 site on ubiquitin (K48O) significantly increased UCHL1-mediated CTTN ubiquitination, whereas the K63O ubiquitin mutation had no effect ( Figure 5H and Supplementary Figure S4C).…”

A noncanonical role of NOD-like receptor NLRP14 in PGCLC differentiation and spermatogenesis

“…However, there are outliers as well. For example, Nlrp4 and Nlrp11 seem to suppress IFN- or TLR-mediated immune responses by ubiquitination and proteasomal degradation, not through the inflammasomes ( 53 , 54 ). Although these reports support that many NLRPs did function through immune-related pathways, the situation for gonad-specific NLRPs seems to be different.…”

Negative Regulation of Cytosolic Sensing of DNA

“…In addition, NLRC5 can suppress TLR signaling by modulating IKK activation (Cui et al, 2010), though NLRC5 deficiency does not affect this signaling pathway (Kumar et al, 2011b). Finally, the primate specific NLRP11 suppresses TLR-mediated activation of NF-κB by targeting TRAF6 for degradation in myeloid cells and B-cells (Ellwanger et al, 2018;Qin et al, 2017b;Wu et al, 2017). Together, these emerging properties call into question whether the established role for this family in activating proinflammatory responses may in fact represent an exception rather than a rule.…”