Type IV Secretion and Signal Transduction of Helicobacter pylori CagA through Interactions with Host Cell Receptors

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.

Biological Diversity and Evolution of Type IV Secretion Systems

“…Furthermore, in addition to VirB5-like CagL, other subunits including CagI, CagH, a domain of CagY and the CagA substrate itself associate with the pilus tip. The surface display of CagL, CagI, CagY, and CagA appears to be biologically relevant in view of evidence that these subunits bind integrin receptors on host epithelial cell surfaces (Backert and Tegtmeyer 2017; Conradi et al 2012). Comparative genomic studies also have supplied evidence for the diversification of surface-localized Cag subunits, presumably under evolutionary selective pressures in the human host (see Chapter “ The Helicobacter pylori Type IV Secretion System Encoded by the cag Pathogenicity Island: Architecture, Function, and Signaling ”).…”

Extraction of molecular features for the drug discovery targeting protein‐protein interaction of Helicobacter pylori CagA and tumor suppressor protein ASSP2

“…Complex interactions between H. pylori virulence agents and host proteins initiate the progression of gastric cancer . During the past several years, the virulent machinery of H. pylori , cag pathogenicity island, has gained considerable attention of many researchers …”

“…machinery of H. pylori, cag pathogenicity island, has gained considerable attention of many researchers. [4][5][6] The most virulent factor of cag pathogenicity island is the cytotoxin-associated gene A (CagA) that is translocated into the epithelial cells through a type IV secretion system (T4SS). 7 H. pylori is classified into two groups named type I and type II strains based on the expression of CagA and another virulent factor VacA.…”

Prevalence of <i>Helicobacter pylori cag</i>A and <i>sab</i>A Genotypes in Patients with Gastric Disease

“…The onset of cancer usually starts with lesions, which evolve into an in- flammation that tends to be followed by chronic gastritis, gastric atrophy, and finally gastric cancer [3]. Its progression is related to genetic characteristics of the host, environmental factors, and the most important parameter: the presence of Helicobacter pylori infection as well as its genotype [4]. H. pylori is a Gram negative, microaerophilic bacterium that colonizes half of the world's population and whose niche is the stomach [4] [5].…”

“…Its progression is related to genetic characteristics of the host, environmental factors, and the most important parameter: the presence of Helicobacter pylori infection as well as its genotype [4]. H. pylori is a Gram negative, microaerophilic bacterium that colonizes half of the world's population and whose niche is the stomach [4] [5]. Its infection is highly successful due to the interaction of this bacterium with the gastric epithelial cells, and for that reason; it is considered one of the most important causes of gastric cancer [6] [7] [8].…”