Helicobacter pylori Employs a Unique Basolateral Type IV Secretion Mechanism for CagA Delivery

Abstract

The Helicobacter pylori (Hp) type IV secretion system (T4SS) forms needle-like pili, whose binding to the integrin-β receptor results in injection of the CagA oncoprotein. However, the apical surface of epithelial cells is exposed to Hp, whereas integrins are basolateral receptors. Hence, the mechanism of CagA delivery into polarized gastric epithelial cells remains enigmatic. Here, we demonstrate that T4SS pilus formation during infection of polarized cells occurs predominantly at basolateral membranes, and not at apical sites. Hp accomplishes this by secreting another bacterial protein, the serine protease HtrA, which opens cell-to-cell junctions through cleaving epithelial junctional proteins including occludin, claudin-8, and E-cadherin. Using a genetic system expressing a peptide inhibitor, we demonstrate that HtrA activity is necessary for paracellular transmigration of Hp across polarized cell monolayers to reach basolateral membranes and inject CagA. The contribution of this unique signaling cascade to Hp pathogenesis is discussed.

Helicobacter pylori Makes a Molecular Incision to Gain Epithelial Entry

“…Prior work had demonstrated that a secreted H. pylori serine protease, HtrA, cleaves E-cadherin to disrupt adherens junctional complexes (Hoy et al, 2010). Tegtmeyer et al now demonstrate that HtrA is secreted in vivo in H. pylori infected patients and functions to cleave gastric epithelial adherens junctions and disrupt mucosal barrier function (Tegtmeyer et al, 2017) (Figure 1). In addition to cleavage of E-cadherin, HtrA also facilitates cleavage of other tight junction proteins, namely occludin and claudin-8, to further disrupt barrier function and increase paracellular permeability (Tegtmeyer et al, 2017) (Figure 1).…”

“…Tegtmeyer et al now demonstrate that HtrA is secreted in vivo in H. pylori infected patients and functions to cleave gastric epithelial adherens junctions and disrupt mucosal barrier function (Tegtmeyer et al, 2017) (Figure 1). In addition to cleavage of E-cadherin, HtrA also facilitates cleavage of other tight junction proteins, namely occludin and claudin-8, to further disrupt barrier function and increase paracellular permeability (Tegtmeyer et al, 2017) (Figure 1). HtrA-mediated cleavage of E-cadherin, occludin, and claudin-8 subsequently permits transmigration of H. pylori from the apical surface to the basolateral cell membrane (Tegtmeyer et al, 2017) (Figure 1).…”

“…In this issue of Cell Host & Microbe , Tegtmeyer et al (2017) show that a secreted bacterial protease disrupts apical-junctional complexes, paving the way for H. pylori to access the basolateral compartment and trigger pathogenesis. …”

“…Using in vivo experiments and polarized cell models, Tegtmeyer et al have now elucidated a unique mechanism by which H. pylori gains access to the basolateral cell surface, thereby facilitating Cag T4SS interactions with the previously identified integrin-α5β1 host cell receptor (Kwok et al, 2007) and targeted injection of CagA (Tegtmeyer et al, 2017) (Figure 1). Prior work had demonstrated that a secreted H. pylori serine protease, HtrA, cleaves E-cadherin to disrupt adherens junctional complexes (Hoy et al, 2010).…”

“…In addition to cleavage of E-cadherin, HtrA also facilitates cleavage of other tight junction proteins, namely occludin and claudin-8, to further disrupt barrier function and increase paracellular permeability (Tegtmeyer et al, 2017) (Figure 1). HtrA-mediated cleavage of E-cadherin, occludin, and claudin-8 subsequently permits transmigration of H. pylori from the apical surface to the basolateral cell membrane (Tegtmeyer et al, 2017) (Figure 1). Following localization to the basolateral cell surface, H. pylori actively assembles and deploys the Cag T4SS, which then directly interacts with its cognate integrin-α5β1 receptor, allowing for translocation of CagA into host cells (Tegtmeyer et al, 2017) (Figure 1).…”