Autoregulatory feedback loops terminating the NF-κB response

Yan²,

Proc. Natl. Acad. Sci. U.S.A.

et al. 2010

134

152

Olfactomedin 4 (OLFM4) is a glycoprotein that has been found to be up-regulated in inflammatory bowel diseases and Helicobacter pylori infected patients. However, its role in biological processes such as inflammation or other immune response is not known. In this study, we generated OLFM4 KO mice to investigate potential role(s) of OLFM4 in gastric mucosal responses to H. pylori infection. H. pylori colonization in the gastric mucosa of OLFM4 KO mice was significantly lower compared with WT littermates. The reduced bacterial load was associated with enhanced infiltration of inflammatory cells in gastric mucosa. Production and expression of proinflammatory cytokines/chemokines such as IL-1β, IL-5, IL-12 p70, and MIP-1α was increased in OLFM4 KO mice compared with infected controls. Furthermore, we found that OLFM4 is a target gene of NF-κB pathway and has a negative feedback effect on NF-κB activation induced by H. pylori infection through a direct association with nucleotide oligomerization domain-1 (NOD1) and -2 (NOD2). Together these observations indicate that OLFM4 exerts considerable influence on the host defense against H. pylori infection acting through NOD1 and NOD2 mediated NF-κB activation and subsequent cytokines and chemokines production, which in turn inhibit host immune response and contribute to persistence of H. pylori colonization.NF-κB | nucleotide oligomerization domain-1 and -2

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Olfactomedin 4 down-regulates innate immunity against Helicobacter pylori infection

Yan²,

Proc. Natl. Acad. Sci. U.S.A.

et al. 2010

134

152

“…Although these studies did not analyse whether the enhanced expression of ARTD10 affected protein level or activity, it is well possible that ARTD10 is part of feedback mechanisms that participate in terminating NF-kB signalling, thereby modulating inflammation. The NF-kB signal transduction pathway is controlled by multiple feedback mechanisms involving, for example, enzymes such as A20 and CYLD that have de-ubiquitinase activity 21 . We have analysed whether ARTD10 is directly responsive to IL-1b or TNFa.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the enhanced poly-ubiquitination of TRAF6 and TAK1 in the presence of ARTD10 suggests that the signal is not propagated properly. The resulting reduction of NF-kB-specific gene expression is expected to inhibit the feedback capacity of the system 21 , which might prolong the stability of poly-ubiquitinated proteins upstream of the interaction point of ARTD10 with the NF-kB signalling pathway. Although the above experiments were performed in the absence of proteasomal inhibitors, we expressed a His-ubiquitin mutant, in which all lysines except K63 were replaced by arginines.…”

Section: Artd10mentioning

confidence: 99%

Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10

et al. 2013

Adenosine diphosphate-ribosylation is a post-translational modification mediated by intracellular and membrane-associated extracellular enzymes and many bacterial toxins. The intracellular enzymes modify their substrates either by poly-ADP-ribosylation, exemplified by ARTD1/PARP1, or by mono-ADP-ribosylation. The latter has been discovered only recently, and little is known about its physiological relevance. The founding member of mono-ADPribosyltransferases is ARTD10/PARP10. It possesses two ubiquitin-interaction motifs, a unique feature among ARTD/PARP enzymes. Here, we find that the ARTD10 ubiquitininteraction motifs bind to K63-linked poly-ubiquitin, a modification that is essential for NF-kB signalling. We therefore studied the role of ARTD10 in this pathway. ARTD10 inhibits the activation of NF-kB and downstream target genes in response to interleukin-1b and tumour necrosis factor-a, dependent on catalytic activity and poly-ubiquitin binding of ARTD10. Mechanistically ARTD10 interferes with poly-ubiquitination of NEMO, which interacts with and is a substrate of ARTD10. Our findings identify a novel regulator of NF-kB signalling and provide evidence for cross-talk between K63-linked poly-ubiquitination and mono-ADPribosylation.

Int Forum Allergy Rhinol

Proinflammatory mediators alter expression of nuclear factor kappa B–regulating deubiquitinases in sinonasal epithelial cells

Wang

Turner

2015

Introduction NF-Kappa B (NF-κB) is a vital transcription factor that is activated by numerous inflammatory stimuli. Its activity is tightly regulated by a family of deubiquitinating enzymes (A20, Cezanne, CYLD) that function in a negative-feedback loop, a process that prevents chronic and systemic inflammation. This study seeks to characterize the expression and functional role of NF-κB-regulating deubiquitinases in the sinonasal epithelium. Methods Expression of A20, Cezanne, and CYLD was assessed in normal sinonasal tissue using immunohistochemistry. Cultured sinonasal epithelial cells were stimulated with pro-inflammatory cytokines (TNF-α, IL-4, IL-13) or LPS and changes in NF-κB activation and deubiquitinase expression were assessed using western blots and quantitative real-time PCR, respectively. Results NF-kB was activated in response to LPS and TNF-α, but not IL-4 or IL-13. A20, Cezanne, and CYLD were all expressed in sinonasal tissue, primarily along the apical surface of the epithelium. Pro-inflammatory mediators primarily affected expression of A20, with upregulation by LPS and TNF-α and downregulation by IL-4 and IL-13. Conclusions The NF-κB-regulating deubiquitinases A20, Cezanne, and CYLD are expressed in sinonasal tissue and are differentially induced by pro-inflammatory cytokines and microbial antigens. These results suggest an important role for NF-κB-regulating deubiquitinases in mucosal immunity and homeostasis.