The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7.
Toll-like receptor 2 (TLR2) plays an important role in host defense against bacterial pathogens. Activation of TLR2 signaling not only induces the activation of innate immunity and instructs the development of the acquired immunity but also leads to the detrimental inflammatory responses in inflammatory and infectious diseases. To avoid detrimental inflammatory responses, TLR2 signaling must be tightly regulated. In contrast to the relative known positive regulation of TLR2 signaling, its negative regulation, however, is largely unknown. In addition the distal signaling components that link TLR2 to its downstream signaling pathways have yet to be further defined. In the present study we have provided direct evidence for the negative regulation of TLR2 signaling by the tumor suppressor cylindromatosis (CYLD). We showed that activation of TLR2 signaling by TLR2 ligands including peptidoglycan (PGN), MALP-2, and Pam3CSK4 induces activation of IKKs-IkappaBalpha and MKK3/6-p38 pathways not only by TRAF6 but also by TRAF7, a recently identified TRAF family member. The activation of both pathways leads to the transcription of TNF-alpha, IL-1beta, and IL-8 as well as CYLD. CYLD in turn leads to the inhibition of TRAF6 and TRAF7 likely via a deubiquitination-dependent mechanism. The present studies thus unveil a novel autoregulatory feedback mechanism that negatively controls TLR2-IKKs-IkappaBalpha/MKK3/6-p38-NF-kappaB-dependent induction of immune and inflammatory responses via negatively cross-talking with both TRAF6 and TRAF7. These findings provide novel insights into autoregulation and negative regulation of TLR signaling.
Yoshida
Hiroki
H
Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, California 90057, USA.
Jono
Hirofumi
H
Kai
Hirofumi
H
Li
Jian-Dong
JD
D017209:Apoptosis; D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D025461:Feedback, Physiological; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation; D007375:Interleukin-1 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008024:Ligands; D055666:Lipopeptides; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D010457:Peptidoglycan / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D020239:Receptor Cross-Talk; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020672:I-kappa B Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D008024:Ligands; D055666:Lipopeptides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009842:Oligopeptides; D010457:Peptidoglycan; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; D048029:TNF Receptor-Associated Factor 6; C486460:TRAF7 protein, human; D051195:Toll-Like Receptor 2; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; C106335:macrophage stimulatory lipopeptide 2; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD