**6. HtrA**

One recently recognized mechanism by which CagA disrupts the barrier is mediated by a HtrA (high-temperature requirement A) serine protease [67]. This enzyme is part of a four proteases specific family identified in *E. coli*, *C. jejuni*, *C. coli* and *H. pylori,* all of which enhance adhesion, cellular invasion, and bacterial transmigration via the paracellular route [68]. The HtrA family of proteases contain a chymotrypsin-like protease domain and at least one C-terminal PDZ domain [69].

HtrA are bacterial proteins that provide tolerance to oxidative and heat stress; they undergo oligomerization when denatured proteins are encountered (**Figure 4**) [70]. HtrA can be expressed at the bacterial cell surface, or transported into the extracellular space, or shed in outer membrane vesicles. It favors bacterial paracellular transmigration by cleaving cell-to-cell junction factors such as components of tight junctions that leads to disruption of the epithelial barrier [71]. It has been shown that HtrA1 expression in gastric cancers correlates with better response to cisplatin-based chemotherapy [72].

Although *H. pylori*-infection and –related gastric diseases are clearly associated with downregulation of E-cadherin [73, 74], the mechanism remained elusive. The

**Figure 4.** *Tridimensional modeling of* H. pylori *trimeric HtrA. From Albrecht et al. [70].*

bacteria disrupts E-cadherin by upregulating the expression of several metalloprotease-1, −3, −7, −9, −10 and ADAM-10 and -15 all of which cleave E-cadherin on the cell surface [6, 68, 75–78]. It has recently been established that HtrA allows access of *H. pylori* to the basolateral side of the gastric epithelium through cleavage of the N-terminal fragment domain of E-cadherin [79] apparently affecting occludin expression on the epithelial cell membrane leading to destruction of adherence junctions and downregulation of the barrier function thus facilitating CagA delivery [80–82]. Phosphorylation of MLC by the specific MLC kinase regulates paracellular permeability [83]. It has been shown that certain strains of *H. pylori* induce the rearrangement of claudin-4 and claudin-5 in a MLC Kinase dependent but in a CagA- and VacA-independent manner [84]; the exact mechanism was not determined although ammonium produced by *H. pylori* urease has been implicated [85, 86].
