Bacterial activation of β-catenin signaling in human epithelia

Sun, Jun; Hobert, Michael E.; Rao, A.R.; Neish, Andrew S.; Madara, James L.

doi:10.1152/ajpgi.00498.2003

Cited by 104 publications

(115 citation statements)

References 28 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…5 Additionally, we showed that AvrA inhibited the NF-kB pathways and consequently modulated cellular inflammation. 27 We believe that the bacterial effector AvrA regulates the activation of NF-kB through b-catenin stabilization.…”

Section: Discussionmentioning

confidence: 90%

“…In contrast, non-pathogenic bacteria stabilize b-catenin by inhibiting b-catenin phosphorylation through GSK-3b and ubiquitination of b-catenin. 5 Stabilization of b-catenin represses NF-kB-dependent inflammatory pathways and inhibits IL-8 secretion during bacterial colonization (Figure 7b). …”

Section: Discussionmentioning

confidence: 99%

“…Bacterial growth conditions were as follows: non-agitated microaerophilic bacterial cultures were prepared by inoculation of 10 ml of Luria-Bertani broth with 0.01 ml of a stationary phase culture, followed by overnight incubation (B18 h) at 371C, as described previously. 5 Cell Culture HCT116 CTNNB1 WT/D45 and its b-catenin knockout derivative lines, HCT116 CTNNB1 À/D45 and CTNNB1 WT/À , were cultured in McCoy's 5A medium supplemented with 10% (vol/vol) fetal bovine serum (FBS). MDCK II cells were grown on permeable supports (0.4 mm pore size) in DMEM supplemented with 10% FBS.…”

Section: Materials and Methods Bacterial Strains And Growth Conditionsmentioning

confidence: 99%

See 2 more Smart Citations

β-Catenin activity negatively regulates bacteria-induced inflammation

Duan

Liao

Kuppireddi

et al. 2007

Laboratory Investigation

Self Cite

142

177

View full text Add to dashboard Cite

Wild-type (WT) Salmonella typhimurium causes acute intestinal inflammation by activating the nuclear factor kappa B (NF-kB) pathway. Interestingly, WT Salmonella infection also causes degradation of b-catenin, a regulator of cellular proliferation. Regulation of b-catenin and the inhibitor of NF-kB, IkBa, is strikingly similar, involving phosphorylation at identical sites, ubiquitination by the same E3 ligase, and subsequent proteasomal degradation. However, how b-catenin directly regulates the NF-kB pathway during bacteria-induced inflammation in vivo is unknown. Using streptomycinpretreated mice challenged with Salmonella, we demonstrated that WT Salmonella stimulated b-catenin degradation and decreased the physical association between NF-kB and b-catenin. Accordingly, WT Salmonella infection decreased the expression of c-myc, a b-catenin-regulated target gene, and increased the levels of IL-6 and TNF-a, the NF-kB-regulated target genes. Bacterial infection directly stimulated phosphorylation of b-catenin, both in vivo and in vitro. Closer examination revealed that glycogen synthase kinase 3b (GSK-3b) kinase activity was increased in response to WT Salmonella, whereas non-virulent Salmonella had no effect. siRNA of GSK-3b was able to stabilize IkBa in response to WT Salmonella. Pretreatment for 24 h with LiCl, an inhibitor of GSK-3b, reduced WT Salmonella induced IL-8 secretion. Additionally, cells expressing constitutively active b-catenin showed IkBa stabilization and inhibition of NF-kB activity not only after WT Salmonella infection but also after commensal bacteria (Escherichia coli F18) and TNF-a treatment. This study suggests a new role for b-catenin as a negative regulator of inflammation. Bacteria pathogenicity requires overcoming or altering many very effective host defense mechanisms, 1 including the activation of nuclear factor kappa B (NF-kB). 2-4 Bacterial invasion of intestinal epithelial cells (IECs) stimulates NF-kB and, interestingly, degradation of b-catenin, 5 a potent transcriptional factor responsible for cellular proliferation and differentiation. It is notable that regulation of b-catenin and the inhibitor of NF-kB, IkBa, are strikingly similar, involving phosphorylation of the same N-terminal serine sequence sites, ubiquitination by the same E3 ligase complex, and subsequent proteasomal degradation. 6,7 To date, no publications have reported on the physiological significance of b-catenin's potential inter-relationship with the NF-kB inflammatory pathway after bacterial infection in vivo.In this study, therefore, we investigated the role of b-catenin in modulating the proinflammatory response mediated by NF-kB subsequent to Salmonella infection in vivo. We examined the possibility that b-catenin functions as a negative regulator of NF-kB, much in the same way as IkBa, through physical interaction with NF-kB. Additionally, we established the role of glycogen synthase kinase 3b (GSK-3b), as the negative regulator of b-catenin's stability and subsequent reactivity with NF-kB in both in vit...

show abstract

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Materials and Methods Bacterial Strains And Growth Conditionsmentioning

confidence: 99%

See 1 more Smart Citation

β-Catenin activity negatively regulates bacteria-induced inflammation

Duan

Liao

Kuppireddi

et al. 2007

Laboratory Investigation

Self Cite

142

177

View full text Add to dashboard Cite

show abstract

“…Interestingly, the YopJ-like molecule from Salmonella typhimurium, AvrA, has been reported to inhibit the NF-B pathway (22) and also to inhibit the degradation of ␤-catenin (23). Phosphorylation of ␤-catenin occurs within a motif that is highly similar to the phosphorylation motif of I B (14) and it has been suggested that IKK␣ may phosphorylate and regulate the deg- radation of ␤-catenin (24).…”

Section: Discussionmentioning

confidence: 99%

Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling

Mittal

Peak‐Chew²,

McMahon³

2006

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

266

278

View full text Add to dashboard Cite

To overcome host defenses, bacterial pathogens of the genus Yersinia inject specific effector proteins into colonized mammalian cells. One such virulence factor, YopJ, inhibits the host inflammatory response and induces apoptosis of immune cells by blocking multiple signaling pathways, including the MAPK and NF-B pathways. In this study, we show that YopJ exerts its deleterious effects by catalyzing the acetylation of two serine residues in the activation loop of the MAP kinase kinase, MEK2. This covalent modification prevents the phosphorylation of these serine residues that is required for activation of MEK2 and downstream signal propagation. We also show that YopJ causes acetylation of a threonine residue in the activation loop of both the ␣ and ␤ subunits of the NF-B pathway kinase, IKK. These results establish a hitherto uncharacterized mode of action for bacterial toxins and suggest the possibility that serine/threonine acetylation may occur even under nonpathogenic conditions and may be a widespread protein modification regulating protein function in eukaryotic cells.inflammation ͉ MEK U nderstanding the mode of action of bacterial toxins has provided insight into the working of mammalian cells especially with regard to signal transduction pathways that impinge upon the activation of the innate immune system (1, 2). Historically, plague has been one of the most devastating diseases to humans, second only to smallpox. The bacillus Yersinia pestis is the causative agent of plague, and two other Yersinia species, Yersinia pseudotuberculosis and Yersinia enterocolitica, cause septicaemic and gastrointestinal disorders (3). These pathogens inject a bouquet of six effector proteins into the mammalian cell cytosol using a type III secretion apparatus (4). These Yersinia outer proteins (Yops) help the pathogen multiply extracellularly in the host by preventing its phagocytosis and by slowing down the onset of the inflammatory response (5). YopE, YopT, and YopO target the Rho family of GTP-binding proteins that control actin cytoskeleton dynamics whereas YopH dephosphorylates focal adhesion proteins, thus inhibiting focal adhesion disassembly. Together, the action of these Yops contributes to the resistance of Yersinia to undergo phagocytosis, a process known to require remodeling of the actin cytoskeleton and of focal adhesions. Suppression of phagocytosis enables Yersinia to evade the macrophage defense network, thereby allowing them to proliferate in Peyer's patches as extracellular microcolonies. The leucine-rich protein, YopM, has been shown to bind to several host cell kinases, resulting in their activation (6). The remaining outer protein, YopJ (also called YopP in Y. enterocolitica) has emerged as an important agent that leads to the reduced host inflammatory response characteristic of Yersinia infections (5). Exposure of macrophages to lipopolysaccharide leads to the activation of NF-B and of several members of the MAPK family that promote the production of proinflammatory cytokines such as TNF-␣. YopJ in...

show abstract

“…Salmonella typhimurium wild-type strain (WT-SL) and nonpathogenic strain PhoP c (28) were used in this study. Nonagitated microaerophilic bacterial cultures were prepared by inoculating 10 ml of Luria-Bertani broth with 0.01 ml of a stationary phase culture followed by overnight incubation (ϳ18 h) at 37°C, as previously described (38).…”

Section: Methodsmentioning

confidence: 99%

Increased NF-κB activity in fibroblasts lacking the vitamin D receptor

Sun

Kong

Duan³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

215

194

View full text Add to dashboard Cite

1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-κB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR−/− mice, the basal level of κB inhibitor (IκB) α protein was markedly decreased compared with VDR+/− MEFs; however, degradation of IκBα and its phosphorylation in response to TNF-α treatment or Salmonella infection were not altered in VDR−/− cells, neither were the levels of IκB kinase-α and IκB kinase-β proteins. Consistent with IκBα reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR−/− cells. In addition, the physical interaction between VDR and p65 was absent in VDR−/− MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-κB transcriptional activity; consistently, induction of IL-6 by TNF-α or IL-1β was much more robust in VDR−/− than in VDR+/− cells, indicating that VDR−/− cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-κB activity. The reduction of IκBα in VDR−/− MEFs may be partially explained by the lack of VDR-mediated stabilization of IκBα by 1,25(OH)2D3. This is supported by the observation that IκBα degradation induced by TNF-α was inhibited by 1,25(OH)2D3 in VDR+/− cells, but not in VDR−/− cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-κB activation.

show abstract

Bacterial activation of β-catenin signaling in human epithelia

Cited by 104 publications

References 28 publications

β-Catenin activity negatively regulates bacteria-induced inflammation

β-Catenin activity negatively regulates bacteria-induced inflammation

Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling

Increased NF-κB activity in fibroblasts lacking the vitamin D receptor

Contact Info

Product

Resources

About