Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system

Abstract

Many Gram-negative pathogens harbor type IV secretion systems (T4SS) that translocate bacterial virulence factors into host cells to hijack cellular processes. The pathology of the gastric pathogen Helicobacter pylori strongly depends on a T4SS encoded by the cag pathogenicity island. This T4SS forms a needle-like pilus, and its assembly is accomplished by multiple protein-protein interactions and various pilus-associated factors that bind to integrins followed by delivery of the CagA oncoprotein into gastric epithelial cells. Recent studies revealed the crystal structures of six T4SS proteins and pilus formation is modulated by iron and zinc availability. All these T4SS interactions are crucial for deregulating host signaling events and disease progression. New developments in T4SS functions and their importance for pathogenesis are discussed.

Keywords: CagA; CagL; CagY; EGF receptor; GTPase; Helicobacter pylori; MARK2/PAR1b kinase; T4SS; VirB proteins; c-Met; cagPAI; cortactin; gastric disease; integrin; signaling; type IV secretion; tyrosine kinases; β-catenin.

Figure 1. Model for the assembled T4SS complex in Helicobacter pylori. (A)

The T4SS encoded by the cag pathogenicity island is a multicomponent protein complex spanning the inner and outer membranes and exhibits homology to the VirB/VirD4 T4SS machinery of Agrobacterium and other Gram-negative bacteria. The Helicobacter pylori T4SS assembly and cellular localization of the proteins are shown in a simplified manner and according to current knowledge. Pilus components, core complex proteins, energetic components and other factors are highlighted in the box as indicated. The reported substrates for this T4SS are CagA and possibly peptidoglycan. We have chosen the cag nomenclature to highlight the various factors, see also Table 1. (B) Scanning electron microscopy of H. pylori infection of AGS gastric epithelial cells. Typical T4SS pili are shown, connecting the bacterium with the host cell membrane (arrows). Scale bar represents 1 μm. For more details see text. T4SS: Type IV secretion system. (A) Adapted with permission from [10] © John Wiley and Sons. (B) Kindly provided by Manfred Rohde (HZI Brausnschweig, Germany) [35] with kind permission from © Nature Publishing. For color figures, please see online at www.futuremedicine.com/doi/full/10.2217/FMB.15.32

Figure 2. Model for the role of Helicobacter pylori T4SS effector proteins in host cell interaction and disease-associated signal transduction

T4SS effectors alter different cellular processes in polarized gastric epithelial cells as illustrated. CagA is translocated into the cytoplasm of infected cells and modulates various signaling cascades associated with cell proliferation, inflammation, motility, cytoskeletal rearrangements, disruption of tight and adherens junctions (AJ and TJ) and suppression of apoptosis or acid secretion, as shown. Receptor tyrosine kinases such as EGFR and c-Met, transcription factors NF-κB and AP-1 as well as small Rho GTPases Rac1 and Cdc42 can also be activated by the T4SS. However, because it is still unclear if integrin-mediated delivery of CagA into the cells occurs at apical and/or basolateral sites, the integrin receptors were indicated at both locations. The various bacterial effectors and host signaling molecules are explained in the bottom box. For more details see text. T4SS: type IV secretion system. Adapted with permission from [44] © John Wiley and Sons.