The conundrum of Helicobacter pylori-associated apoptosis in gastric cancer.

Helicobacter pylori is a human microbial pathogen that colonizes the gastric epithelium and causes type B gastritis with varying degrees of active inflammatory infiltrates. The underlying chronic inflammation induced by H. pylori and other environmental factors may promote the development of neoplasms and adenocarcinoma of the stomach. Dysregulation of various cellular processes in the gastric epithelium and in different cells of the microenvironment is a hallmark of H. pylori infection. We address the conundrum of H. pylori-associated apoptosis and review distinct mechanisms induced in host cells that either promote or suppress apoptosis in gastric epithelial cells, often simultaneously. We highlight key processes in the microenvironment that contribute to apoptosis and gastric carcinogenesis.

A20 undermines alternative NF-κB activity and expression of anti-apoptotic genes in Helicobacter pylori infection.

A hallmark of infection by the pathogen Helicobacter pylori, which colonizes the human gastric epithelium, is the simultaneous activation of the classical and alternative nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, underlying inflammation and cell survival. Here, we report that the classical NF-κB target gene product A20 contributes to the negative regulation of alternative NF-κB signaling in gastric epithelial cells infected by H. pylori. Mechanistically, the de novo synthesized A20 protein interacts with tumor necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA) and thereby interferes with the association of TIFA with the NIK regulatory complex. We also show that alternative NF-κB activity contributes to the up-regulation of anti-apoptotic genes, such as baculoviral IAP repeat containing 2 (BIRC2), BIRC3 and B-cell lymphoma 2-related protein A1 (BCL2A1) in gastric epithelial cells. Furthermore, the observed over-expression of RelB in human gastric biopsies with type B gastritis and RelB-dependent suppression of apoptotic cell death emphasize an important role of the alternative NF-κB pathway in H. pylori infection.

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

Helicobacter pylori infection constitutes one of the major risk factors for the development of gastric diseases including gastric cancer. The activation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) via 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-κB activation, but its role in alternative NF-κB 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 TGFß-activated kinase 1 (TAK1), leading to the activation of classical NF-κB signaling, 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-κB pathway. Our findings therefore establish a dual function of TIFA in the activation of classical and alternative NF-κB signaling in H. pylori-infected gastric epithelial cells.

NF-kappaB-inducing kinase in cancer.

Dysregulation of the alternative NF-κB signaling has severe developmental consequences that can ultimately lead to oncogenesis. Pivotal for the activation of the alternative NF-κB pathway is the stabilization of the NF-κB-inducing kinase (NIK). The aim of this review is to focus on the emerging role of NIK in cancer. The documented subversion of NIK in cancers highlights NIK as a possible therapeutic target. Recent studies show that the alterations of NIK or the components of its regulatory complex are manifold including regulation on the transcript level, copy number changes, mutations as well as protein modifications. High NIK activity is associated with different human malignancies and has adverse effects on tumor patient survival. We discuss here research focusing on deciphering the contribution of NIK towards cancer development and progression. We also report that it is possible to engineer inhibitors with high specificity for NIK and describe developments in this area.

Pathogen-induced ubiquitin-editing enzyme A20 bifunctionally shuts off NF-κB and caspase-8-dependent apoptotic cell death.

The human pathogen Helicobacter pylori infects more than half of the world's population and is a paradigm for persistent yet asymptomatic infection but increases the risk for chronic gastritis and gastric adenocarcinoma. For successful colonization, H. pylori needs to subvert the host cell death response, which serves to confine pathogen infection by killing infected cells and preventing malignant transformation. Infection of gastric epithelial cells by H. pylori provokes direct and fast activation of the proinflammatory and survival factor NF-κB, which regulates target genes, such as CXCL8, BIRC3 and TNFAIP3. However, it is not known how H. pylori exploits NF-κB activation and suppresses the inflammatory response and host apoptotic cell death, in order to avert the innate immune response and avoid cell loss, and thereby enhance colonization to establish long-term infection. Here we assign for the first time that H. pylori and also Campylobacter jejuni-induced ubiquitin-editing enzyme A20 bifunctionally terminates NF-κB activity and negatively regulates apoptotic cell death. Mechanistically, we show that the deubiquitinylase activity of A20 counteracts cullin3-mediated K63-linked ubiquitinylation of procaspase-8, therefore restricting the activity of caspase-8. Interestingly, another inducible NF-κB target gene, the scaffold protein p62, ameliorates the interaction of A20 with procaspase-8. In conclusion, pathogen-induced de novo synthesis of A20 regulates the shut-off of the survival factor NF-κB but, on the other hand, also impedes caspase-8-dependent apoptotic cell death so as to promote the persistence of pathogens.