The Helicobacter pylori cag pathogenicity island as a determinant of gastric cancer risk

Abstract

Helicobacter pylori strains can be broadly classified into two groups based on whether they contain or lack a chromosomal region known as the cag pathogenicity island (cag PAI). Colonization of the human stomach with cag PAI-positive strains is associated with an increased risk of gastric cancer and peptic ulcer disease, compared to colonization with cag PAI-negative strains. The cag PAI encodes a secreted effector protein (CagA) and components of a type IV secretion system (Cag T4SS) that delivers CagA and non-protein substrates into host cells. Animal model experiments indicate that CagA and the Cag T4SS stimulate a gastric mucosal inflammatory response and contribute to the development of gastric cancer. In this review, we discuss recent studies defining structural and functional features of CagA and the Cag T4SS and mechanisms by which H. pylori strains containing the cag PAI promote the development of gastric cancer and peptic ulcer disease.

Keywords: Helicobacter pylori; bacterial secretion system; effector protein; gastric cancer; inflammation.

Figure 1.

Organization of genes within the cag PAI. Five genes encoding proteins localized to the T4SS OMCC^, and three genes encoding putative ATPases localized to the T4SS IMC are indicated. Genes required for Cag T4SS activity that lack homologs in other bacterial species are indicated with diagonal stripes.

Figure 2.

Cag T4SS-mediated delivery of CagA and non-protein substrates into host cells. The Cag T4SS is required for delivery of CagA, LPS metabolites, peptidoglycan and DNA into host cells. Each substrate elicits a cellular response. CagA is phosphorylated by tyrosine kinases (such as Src), and phosphorylated CagA can cause disruptions to a variety of signaling pathways. LPS metabolites and peptidoglycan elicit NF-κB activation, leading to IL-8 production. DNA translocation causes TLR9 activation. Created with BioRender.com.

Figure 3.

Structural organization of the Cag T4SS OMCC. The 14-fold-symmetric OMC and 17-fold-symmetric PR are illustrated.^, (a, b, c) conserved Cag T4SS components. Purple = CagY, yellow = CagX, pink = CagT. (d, e, f) H. pylori-specific T4SS components. Blue = Cag3, green = CagM.