Abstract
Helicobacter pylori is a highly successful human bacterium, which is exceptionally equipped to persistently inhabit the human stomach. Colonization by this pathogen is associated with gastric disorders ranging from chronic gastritis and peptic ulcers to cancer. Highly virulent H. pylori strains express the well-established adhesins BabA/B, SabA, AlpA/B, OipA, and HopQ, and a type IV secretion system (T4SS) encoded by the cag pathogenicity island (PAI). The adhesins ascertain intimate bacterial contact to gastric epithelial cells, while the T4SS represents an extracellular pilus-like structure for the translocation of the effector protein CagA. Numerous T4SS components including CagI, CagL, CagY, and CagA have been shown to target the integrin-β1 receptor followed by translocation of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine and CagA-containing outer membrane vesicles may also play a role in the delivery process. Translocated CagA undergoes tyrosine phosphorylation in C-terminal EPIYA-repeat motifs by oncogenic Src and Abl kinases. CagA then interacts with an array of host signaling proteins followed by their activation or inactivation in phosphorylation-dependent and phosphorylation-independent fashions. We now count about 25 host cell binding partners of intracellular CagA, which represent the highest quantity of all currently known virulence-associated effector proteins in the microbial world. Here we review the research progress in characterizing interactions of CagA with multiple host cell receptors in the gastric epithelium, including integrin-β1, EGFR, c-Met, CD44, E-cadherin, and gp130. The contribution of these interactions to H. pylori colonization, signal transduction, and gastric pathogenesis is discussed.
Highlights
Helicobacter pylori colonizes the stomach in about 50% of the human world population and is associated with chronic, often asymptomatic gastritis in all infected people
Akt kinase directly phosphorylates and thereby inhibits GSK-3β, leading to impaired phosphorylation and stabilization of the β-catenin protein [111]. In agreement with these observations, pharmacological inhibition or siRNA knockdown of Akt kinase restored serine/threonine phosphorylation of β-catenin [114]. These results indicate that perturbation of the E-cadherin/β-catenin complex as well as Akt and GSK-3β signaling induced by H. pylori CagA play important roles in host cell proliferation and the development of intestinal metaplasia and gastric cancer
The investigation of bacteria-host interactions and virulence factors such as the T4SS and CagA have provided us with crucial insights into the mechanisms leading to H. pylori pathogenesis
Summary
Helicobacter pylori colonizes the stomach in about 50% of the human world population and is associated with chronic, often asymptomatic gastritis in all infected people. A number of T4SS proteins, including CagL, CagY, CagI, and CagA, are exposed at the pilus surface where they can interact with the integrin α5 β1 host receptor followed by the translocation of CagA in epithelial cells [24,25,26,27,28]. Translocated CagA dysregulates the homeostatic signal transduction of gastric epithelial cells involved in chronic inflammation and malignancy by changing cell polarity, apoptosis, and proliferation [39,40,41]. Because of these cancer-promoting activities, CagA has been called the first bacterial oncoprotein [42].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
