Article

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

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nature Immunology (Impact Factor: 24.97). 08/2012; 13(9):823-31. DOI: 10.1038/ni.2378
Source: PubMed

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.

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    • "Finally, there remain many NLRs whose respective roles in host defense and/or physiology are just beginning to be appreciated, such as NLRP10 (Eisenbarth et al. 2012), NLRC5 (Cui et al. 2010; Meissner et al. 2010b), NLRC3 (Schneider et al. 2012; Zhang et al. 2014), and many more whose functions are still completely unknown. With these NLRs, one of the major hurdles to overcome seems to be identifying the activating signals. "
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    Cold Spring Harbor perspectives in biology 10/2014; 6(12). DOI:10.1101/cshperspect.a016287 · 8.23 Impact Factor
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    • "TRAF6 possesses a unique receptor-binding specificity as the signalling mediator for the TNF receptor super family and TLR super family induced by NF-κB activation. The NF-κB TF is important in inflammation, immune response, cellular proliferation, apoptosis, tumourigenesis, and invasion [50]. Previous studies demonstrated that constitutive activation of NF-κB is an important regulator of genes involved in tumourigenesis, invasion, and migration. "
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    • "While NLRP12, NLRX1, and NLRC3 each influence a variety of signaling pathways, the convergence on NF-κB signaling appears to be a common strategy among the NLRs in this functional sub-group to attenuate inflammation (Figure 1). Additional mechanistic studies have revealed prevalent NLR–TRAF interactions in these models and support the emerging hypothesis that these NLRs function to inhibit NF-κB signaling through the formation of a multi-protein “TRAFasome” complex (54). Dysregulated NF-κB signaling and the additional pathways modulated by these NLRs are critical features in cancer initiation and progression. "
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