**5. CagA**

Of major relevance for this review is the effector protein CagA, one of the most important virulence factors [44, 45]. The cytotoxin-associated gene pathogenicity island (cagPAI) comprises 30 genes [46]. The cytotoxin-associated gene A is a 125-140 kDa protein encoded by the cag pathogenicity island [47], a chromosomal region that simultaneously encodes a type IV secretion system specialized in transferring peptidoglycan and CagA to the cytosol of the target cell in an ATPdependent manner [45, 48]; once translocated, it interacts with numerous proteins in a phosphorylation dependent and independent manner within the epithelial cells, stimulating inflammatory responses, perturbing intracellular actin trafficking, and disrupting cellular tight junctions probably via the ERK1/2 signaling pathway [49–51]. Phosphorylated CagA interacts with Shp2, a host protein that binds to CagA, this complex dephosphorylates the focal adhesion kinase and in turn activates a signal pathway that involves ERK proteins [52, 53]. The transferred peptidoglycan promotes the activation of the pattern-recognition molecule Nod1 within the cytosol of the host cell [54] and subsequently induces the expression of IL-6 and IL-8 as well as MAPK phosphorylation [55–57]. The phosphorylation independent activity of CagA disrupts E-cadherin and ZO-1 and consequently cell-to-cell junctions in polarized epithelial cells [10, 49, 58, 59]. CagA modifies the

#### *Effect of* Helicobacter pylori *on Tight Junctions in Gastric Epithelia DOI: http://dx.doi.org/10.5772/intechopen.96607*

polarity of the infected cells by interacting with Par1b/MARK-2 [60, 61]. CagA also stimulates the expression of NfkB, which subsequently activates the IL-8 promoter and stimulates the release of the chemokine IL-8 into the gastric lumen [62], which disrupts epithelial tight junctions organization [63].

CagA is known to affect intercellular junctions and disrupt junction-mediated functions [64] as it causes an ectopic assembly of tight-junction components by recruiting ZO-1 and JAM to sites of bacterial attachment (Amieva 2003), and disrupts the epithelial barrier function [10]. CagA colocalizes with ZO-1 and JAM proteins, binds Par1b and, by inhibiting atypical PKC-mediated phosphorylation of Par1b, disrupts cell polarity and consequently tight junctions. CagA also targets Cdx2 and therefore claudin-2 expression thus suggesting a novel mechanism for gastric epithelial cells dedifferentiation [65]. Another pathophysiological mechanism by which *H. pylori* affect the epithelial barrier is by Rho kinase dependent manner that induces IL-1R type 1 phosphorylation and claudin-4 expression [66].
