The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB

Abstract

Several members of the NLR family of sensors activate innate immunity. In contrast, we found here that NLRC3 inhibited Toll-like receptor (TLR)-dependent activation of the transcription factor NF-κB by interacting with the TLR signaling adaptor TRAF6 to attenuate Lys63 (K63)-linked ubiquitination of TRAF6 and activation of NF-κB. We used bioinformatics to predict interactions between NLR and TRAF proteins, including interactions of TRAF with NLRC3. In vivo, macrophage expression of Nlrc3 mRNA was diminished by the administration of lipopolysaccharide (LPS) but was restored when cellular activation subsided. To assess biologic relevance, we generated Nlrc3−/− mice. LPS-treated Nlrc3−/− macrophages had more K63-ubiquitinated TRAF6, nuclear NF-κB and proinflammatory cytokines. Finally, LPS-treated Nlrc3−/− mice had more signs of inflammation. Thus, signaling via NLRC3 and TLR constitutes a negative feedback loop. Furthermore, prevalent NLR-TRAF interactions suggest the formation of a ‘TRAFasome’ complex.

Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella)

“…TRIF activates NF-jB through the TIR domain-mediated interaction with TRAF6; meanwhile, TRIF also activate NF-jB through its C-terminal RIP homotypic interaction motif (RHIM), which is responsible for recruiting RIP to TRIF Jiang et al, 2004). However, CiTRIF lacks TRAF6-binding motif (Wu and Arron, 2003;Schneider et al, 2012) and RHIM motif (Sun et al, 2002;Kaiser et al, 2008) through comprehensive sequence analyses. After examining zebrafish TRIF protein sequence, both TRAF6-binding motif and RHIM motif are also undetectable.…”

LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria

“…16). Thus, these data demonstrate that LRRC19 may mediate K63-linked ubiquitination of TARF6, which can promote downstream signalling 31 . Notably, the inhibition of K48-linked ubiquitination of TRAF6 was observed in the presence of LRRC19 (Supplementary Figs 11 and 17), however, the presence of LRRC19 indeed caused decrease and uniquitination of TRAF6 (Fig.…”

Cellular and molecular regulation of innate inflammatory responses

“…[101][102][103] On the contrary, NOD2 deficiency increases TLR2-mediated activation of NF-κB and dysregulated TLR2 in NOD2-deficient mice causes the development of antigenspecific colitis. 104,105 Not only NOD2, many other NLRs play inhibitory roles in regulating the signaling of TLRs: for NLRX1 and NLRC3 via interfering with the TRAF6-NF-κB signaling; 61,106,107 for NLRC5 via interacting with and blocking phosphorylation of IκB kinase α (IKKα) and IKKβ; 59 for NRLP6 and NLRP12 via targeting MAPK and NF-κB activation; 108,109 for NLRC4 via downregulating TLR5-mediated antibody immune responses against flagellin. 110 These synergistic or antagonistic interactions across these three PRR families contribute to a cross-linked and finely tuned network of PRR signaling in response to the large repertoire of PAMPs and ensures the most effective and proper outcomes of innate immune responses.…”