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.
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ABSTRACT: Pancreatic cancer is one of the most lethal malignancies, with a poor response to chemotherapy and therefore it is important to identify novel therapeutic targets. TNF receptor-associated factor 6 (TRAF6) , a regulator of NF-κB signaling, has been found recently to be involved in tumorigenesis. However, its function in pancreatic cancer remains poorly understood. Here, we found that the expression of TRAF6 was up-regulated in pancreatic cancer tissues. Moreover, over-expression of TRAF6 in pancreatic cancer cells promoted cell proliferation and migration, whereas down-regulation of TRAF6 impaired the tumorigenicity of pancreatic cancer cells in vitro and in vivo. Mechanistically, TRAF6 regulated the expression of multiple genes involved in cell growth, apoptosis and migration. Our results suggested several important roles of TRAF6 in the pathogenesis of pancreatic cancer. TRAF6 might therefore represent a potential therapeutic target.Medical Oncology 11/2014; 31(11):260. DOI:10.1007/s12032-014-0260-9 · 2.06 Impact Factor
Article: The multifaceted nature of NLRP12[Show abstract] [Hide abstract]
ABSTRACT: NLRs are a class of cytoplasmic PRRs with various functions, ranging from pathogen/damage sensing to the modulation of inflammatory signaling and transcriptional control of MHC and related genes. In addition, some NLRs have been implicated in preimplantation and prenatal development. NLRP12 (also known as RNO, PYPAF7, and Monarch-1), a member of the family containing an N-terminal PYD, a NBD, and a C-terminal LRR region, is one of the first described NLR proteins whose role remains controversial. The interest toward NLRP12 has been boosted by its recent involvement in colon cancer, as well as in the protection against some severe infections, such as that induced by Yersinia pestis, the causative agent of plague. As NLRP12 is mainly expressed by the immune cells, and its expression is down-regulated in response to pathogen products and inflammatory cytokines, it has been predicted to play a role as a negative regulator of the inflammatory response. Herein, we present an overview of the NLR family and summarize recent insights on NLRP12 addressing its contribution to inflammatory signaling, host defense, and carcinogenesis.Journal of Leukocyte Biology 09/2014; 96(6). DOI:10.1189/jlb.3RU0514-265RR · 4.30 Impact Factor
Article: Inflammasomes[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 · 8.23 Impact Factor