Regulation of Flip Expression and Apoptosis Signaling by Helicobacter Pylori

Helicobacter pylori (HP), a common human pathogen, is associated with duodenal ulcer, peptic ulcer diseases, gastric cancer and MALToma. Recent studies have indicated that T lymphocytes play an important role in the pathogenesis of HP gastritis and MALToma. Previous our studies in collaboration with Professor Hsu (NTU) have demonstrated that HP sensitize human gastric epithelial cells conferred susceptibility to TRAIL-mediated apoptosis via enhanced death receptor signaling. These results suggest a role for immune-mediated apoptosis of gastric epithelial cells by infiltrating T cells during Helicobacter infection. Modulation of host apoptosis signaling by microbial interaction adds a new dimension to the pathogenesis of HP infection. However, the induction of TRAIL-mediated apoptosis and the immunopathogenic mechanism(s) of mucosal damage in HP infections are still not clear. Our previous studies have shown that H. pylori induce TRAIL sensitivity in gastric epithelial cells via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) and activation of caspase 8 downstream pathway through down-regulation of the short form of cellular FLICE-inhibitory protein (FLIP), leading to break apoptosis resistance. Over-expression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells, and the effects of HP-induced FLIP downregulation was inhibited by protesome inhibitor MG132 .This result implies that HP may decrease FLIP by inducing its degradation through interaction with host cells. In this project, we will study the molecular mechanisms determined the regulation of FLIP expression and apoptosis signaling by HP. We have intensively checked the possible upstream signaling molecules of FLIP, and found the phosphorylation of Akt is associated with FLIP expression., suggesting that HP downregulate FLIP expression by protein degradation via inhibiting Akt phosphorylation. This implies the importance of Akt pathway in regulation of FLIP and HP -induced TRAIL apoptosis signaling. To further explore how HP induces Akt/FLIP pathways in gastric epithelial cells is, here in this project, we will further investigate the link between interaction of HP with host cells and FLIP, focused on Akt pathway in regulation of FLIP downregulation, including the possible downstream kinase/ubiquitination, and the upstream signaling pathways leading to regulate Akt/FLIP by HP. In addition, we will study the possible innate sensing pathways to regulate Akt/FLIP after interaction with HP, including TLR and C-type lectin pathways. Finally, to further identification of the key factors/kinases in HP-induced regulation of FLIP degradation and induction of TRAIL apoptosis signaling, we will investigate the gene expression after interaction with HP by using gene profiling to analyze the transcriptome and by RNA sequencing approach. This study will help us to understand the mechanisms of apoptosis signaling modulated by HP, and thereby to identify key factors which may help to design treatment of HP-associated diseases.