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TIFA has dual functions in Helicobacter pylori-induced classical and alternative NF-kB pathways

ABSTRACT: Helicobacter pylori infection constitutes one of the major risk factors for the development of gastric diseases including gastric cancer. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) via the classical and alternative pathways is a hallmark of H. pylori infection leading to inflammation in gastric epithelial cells. Tumor necrosis factor receptor associated factor (TRAF) interacting protein with forkhead-associated domain (TIFA) was previously suggested to trigger classical NF-kB activation but its role in alternative NF-kB activation remains unexplored. Here, we identify TRAF6 and TRAF2 as binding partners of TIFA contributing to the formation of TIFAsomes upon H. pylori infection. Importantly, the TIFA/TRAF6 interaction enables binding of TGFb-activated kinase 1 (TAK1), leading to the activation of classical NF-kB, while the TIFA/TRAF2 interaction causes the transient displacement of cellular inhibitor of apoptosis 1 (cIAP1) from TRAF2 and proteasomal degradation of cIAP1 to facilitate the activation of the alternative NF-kB. Our findings therefore establish a dual function of TIFA in the activation of classical and alternative NF-kB in H. pylori infected gastric epithelial cells.

SUBMITTER: Prof. Michael Naumann

PROVIDER: S-SCDT-EMBOR-2021-52878V1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:AimTo elucidate the sequential gene expression profile in AGS cells co-cultured with wild-type Helicobacter pylori (H pylori) as a model of H pylori-infected gastric epithelium, and to further examine the contribution of cag-pathogenicity islands (cagPAI)-coding type IV secretion system and the two pathways, nuclear factor kappa B (NF-kappaB) and extracellular signal-regulated kinases (ERK) on wild-type H pylori-induced gene expression.MethodsGene expression profiles induced by H pylori were evaluated in AGS gastric epithelial cells using cDNA microarray, which were present in the 4 600 independent clones picked up from the human gastric tissue. We also analyzed the contribution of NF-kappaB and ERK signaling on H pylori-induced gene expression by using inhibitors of specific signal pathways. The isogenic mutant with disrupted cagE (Delta cagE) was used to elucidate the role of cagPAI-encoding type IV secretion system in the gene expression profile.ResultsAccording to the expression profile, the genes were classified into four clusters. Among them, the clusters characterized by continuous upregulation were most conspicuous, and it contained many signal transducer activity-associated genes. The role of cagPAI on cultured cells was also investigated using isogenic mutant cagE, which carries non-functional cagPAI. Then the upregulation of more than 80% of the induced genes (476/566) was found to depend on cagPAI. Signal transducer pathway through NF-kappaB or ERK are the major pathways which are known to be activated by cagPAI-positive H pylori. The role of these pathways in the whole signal activation by cagPAI-positive H pylori was analyzed. The specific inhibitors against NF-kappaB or ERK pathway blocked the activation of gene expression in 65% (367/566) or 76% (429/566) of the genes whose activation appealed to depend on cagPAI.ConclusionThese results suggest that more than half of the genes induced by cagPAI-positive H pylori depend on NF-kappaB and ERK signaling activation, and these pathways may play a role in the gene expression induced by host-bacterial interaction which may associate with H pylori-related gastro-duodenal diseases.

Project description:Helicobacter pylori (H. pylori) classified as a class I carcinogen by the World Health Organization (WHO) plays an important role in the progression of chronic gastritis and the development of gastric cancer. A major bioactive component of Evodia rutaecarpa, evodiamine, has been known for its anti-bacterial effect and anti-cancer effects. However, the inhibitory effect of evodiamine against H. pylori is not yet known and the inhibitory mechanisms of evodiamine against gastric cancer cells are yet to be elucidated concretely. In this study, therefore, anti-bacterial effect of evodiamine on H. pylori growth and its inhibitory mechanisms as well as anti-inflammatory effects and its mechanisms of evodiamine on H. pylori-induced inflammation were investigated in vitr. Results of this study showed the growth of the H. pylori reference strains and clinical isolates were inhibited by evodiamine. It was considered one of the inhibitory mechanisms that evodiamine downregulated both gene expressions of replication and transcription machineries of H. pylori. Treatment of evodiamine also induced downregulation of urease and diminished translocation of cytotoxin-associated antigen A (CagA) and vacuolating cytotoxin A (VacA) proteins into gastric adenocarcinoma (AGS) cells. This may be resulted from the reduction of CagA and VacA expressions as well as the type IV secretion system (T4SS) components and secretion system subunit protein A (SecA) protein which are involved in translocation of CagA and VacA into host cells, respectively. In particular, evodiamine inhibited the activation of signaling proteins such as the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) pathway induced by H. pylori infection. It consequently might contribute to reduction of interleukin (IL)-8 production in AGS cells. Collectively, these results suggest anti-bacterial and anti-inflammatory effects of evodiamine against H. pylori.

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TIFA has dual functions in Helicobacter pylori-induced classical and alternative NF-kB pathways

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