Tip-α (hp0596 Gene Product) Is a Highly Immunogenic Helicobacter pylori Protein Involved in Colonization of Mouse Gastric Mucosa

Abstract

A product of the Helicobacter pylori hp0596 gene (Tip-a) is a highly immunogenic homodimeric protein, unique for this bacterium. Cell fractionation experiments indicate that Tip-a is anchored to the inner membrane. In contrast, the three-dimensional model of the protein suggests that Tip-a is soluble or, at least, largely exposed to the solvent. hp0596 gene knockout resulted in a significant decrease in the level of H. pylori colonization as measured by real-time PCR assay. In addition, the Tip-a recombinant protein was determined to stimulate macrophage to produce IL-1a and TNF-a. Both results imply that Tip-a is rather loosely connected to the inner membrane and potentially released during infection.

Nucleolin as cell surface receptor for tumor necrosis factor-α inducing protein: a carcinogenic factor of Helicobacter pylori

“…Tipa-deficient H. pylori reduces colonization in mouse gastric mucosa (Godlewska et al 2008), and vaccinations with Tipa and del-Tipa also effectively prevented colonization of H. pylori in the stomach of mice (Inoue et al 2009). Therefore, we think that targeting molecules, which inhibit the interaction of Tipa and cell surface nucleolin, will be useful tools for the prevention of inflammation induced by H. pylori infection and of H. pylori-infection itself.…”

“…Tipa directly induces TNF-a gene expression in gastric epithelial cells (Suganuma et al 2005(Suganuma et al , 2006(Suganuma et al , 2008. The unique features of Tipa protein are as follows: (1) H. pylori lacking Tipa gene reduced the colonization levels of H. pylori in the stomach of mice (Godlewska et al 2008); (2) Vaccination with Tipa significantly reduced colonization of H. pylori in mice associated with high levels of Tipa-specific antibody (Inoue et al 2009); (3) Tipa protein is secreted from H. pylori but not mediated through Type IV secretion system (Suganuma et al 2005); and (4) clinical isolates of H. pylori obtained from gastric cancer patients secreted Tipa protein in larger amounts than did H. pylori from patients with simple gastritis (Suganuma et al 2008), strongly suggesting that Tipa plays an important role in H. pylori-induced inflammation and cancer development in human stomach (Balkwill 2009). All these features are different from those of other virulence factors, such as the cag pathogenicity island (cagPAI), CagA (cytotoxin associated antigen) and VacA (vacuolating cytotoxin A).…”

Crystal Structure of the TNF-α-Inducing Protein (Tipα) from Helicobacter pylori: Insights into Its DNA-Binding Activity

“…A cell fractionation experiment indicates that Tipα is anchored to the inner membrane of H. pylori. 7,8 Tipα is secreted as a homodimer of the mature polypeptide (residues , which contains the only two cysteines (Cys25 and Cys27) of Tipα in the N-terminus for the possible formation of interchain disulfide bonds (Fig. 1).…”

“…12 Prediction of the three-dimensional model of Tipα by sequence structure threading suggested that it may adopt a four-α-helical-bundle fold. 7 However, a detailed three-dimensional structure of Tipα is required to provide a structural basis for a better understanding of DNA binding by Tipα and, thus, the carcinogenic mechanism of Tipα. In this study, we have determined the crystal structure of Tipα from H. pylori by way of the multiwavelength anomalous diffraction (MAD) method of X-ray crystallography.…”

How the Discovery of TNF-α Has Advanced Gastrointestinal Diseases and Treatment Regimes

“…H. pylori induces secretion of TNF-a and other pro-inflammatory cytokines in the gastric microenvironment by the expression of Tipa, a bacterial protein unique to H. pylori required for colonization that triggers macrophage TNF-a secretion and activates Ras, a well-known oncogene [28,29]. The mechanisms by which TNF-a promote gastric cancer, however, are still unclear and are likely to be multifactorial.…”