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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1β and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease.
Cold Spring Harbor perspectives in biology 10/2014; 6(12). DOI:10.1101/cshperspect.a016287 · 8.68 Impact Factor
"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 . Previous studies demonstrated that constitutive activation of NF-κB is an important regulator of genes involved in tumourigenesis, invasion, and migration. "
[Show abstract][Hide abstract] ABSTRACT: JMJD2A is a lysine trimethyl-specific histone demethylase that is highly expressed in a variety of tumours. The role of JMJD2A in tumour progression remains unclear. The objectives of this study were to identify JMJD2A-regulated genes and understand the function of JMJD2A in p53-null neuroectodermal stem cells (p53−/− NE-4Cs). We determined the effect of LPS as a model of inflammation in p53−/− NE-4Cs and investigated whether the epigenetic modifier JMJD2A alter the expression of tumourigenic inflammatory genes. Global gene expression was measured in JMJD2A knockdown (kd) p53−/− NE-4Cs and in LPS-stimulated JMJD2A-kd p53−/− NE-4C cells. JMJD2A attenuation significantly down-regulated genes were Cdca2, Ccnd2, Ccnd1, Crebbp, IL6rα, and Stat3 related with cell cycle, proliferation, and inflammatory-disease responses. Importantly, some tumour-suppressor genes including Dapk3, Timp2 and TFPI were significantly up-regulated but were not affected by silencing of the JMJD2B. Furthermore, we confirmed the attenuation of JMJD2A also down-regulated Cdca2, Ccnd2, Crebbp, and Rest in primary NSCs isolated from the forebrains of E15 embryos of C57/BL6J mice with effective p53 inhibitor pifithrin-α (PFT-α). Transcription factor (TF) motif analysis revealed known binding patterns for CDC5, MYC, and CREB, as well as three novel motifs in JMJD2A-regulated genes. IPA established molecular networks. The molecular network signatures and functional gene-expression profiling data from this study warrants further investigation as an effective therapeutic target, and studies to elucidate the molecular mechanism of JMJD2A-kd-dependent effects in neuroectodermal stem cells should be performed.
Experimental Cell Research 09/2014; 328(2). DOI:10.1016/j.yexcr.2014.08.029 · 3.25 Impact Factor
"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. "
[Show abstract][Hide abstract] ABSTRACT: Aberrant inflammation is an enabling characteristic of tumorigenesis. Thus, signaling cascades that alter inflammatory activation and resolution are of specific relevance to disease pathogenesis. Pattern recognition receptors (PRRs) are essential mediators of the host immune response and have emerged as critical elements affecting multiple facets of tumor pathobiology. The nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins are intracellular PRRs that sense microbial and non-microbial products. Members of the NLR family can be divided into functional sub-groups based on their ability to either positively or negatively regulate the host immune response. Recent studies have identified a novel sub-group of non-inflammasome forming NLRs that negatively regulate diverse biological pathways associated with both inflammation and tumorigenesis. Understanding the mechanisms underlying the function of these unique NLRs will assist in the rationale design of future therapeutic strategies targeting a wide spectrum of inflammatory diseases and cancer. Here, we will discuss recent findings associated with this novel NLR sub-group and mechanisms by which these PRRs may function to alter cancer pathogenesis.
Frontiers in Immunology 04/2014; 5:169. DOI:10.3389/fimmu.2014.00169
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