H. pyloriselectively blocks EGFR endocytosis via the non-receptor kinase c-Abl and CagA

Abstract

SummaryHelicobacter pylori infection is a primary cause of peptic ulcers and is associated with gastric carcinogenesis. The H. pylori-induced pathophysiology may be linked to the deregulation of EGFR signalling. Elevated mucosal levels of EGF and the EGFR have been found in antral gastric biopsies of H. pylori-infected patients. A critical mechanism for regulating EGFR signalling is ligand-induced endocytosis. The internalized receptor recycles back to the plasma membrane for continued signalling or is targeted for degradation terminating receptor signalling. Here, we show that H. pylori blocks EGFR endocytosis and receptor degradation upon prolonged infection of gastric epithelial cells. Moreover, this inhibition occurs via a CagA-dependent, but CagA phosphorylationindependent activation of the non-receptor kinase c-Abl, which in turn phosphorylates the EGFR target site pY1173. This suggests a novel CagAinduced host cell response that is independent of CagA tyrosine phosphorylation. Our data indicate an intriguing strategy of H. pylori in host cell manipulations by altering selective receptor populations via a CagA-dependent endocytic mechanism. Furthermore, we identified a new role for c-Abl in phosphorylation of the EGFR target site pY1173 during H. pylori infection.

Multifunctional Abl kinases in health and disease

“…Subsequent reports showed that Abl kinases are also required for infection by several bacteria (e.g. Helicobacter pylori, EPEC, Salmonella enterica, Anaplasma phagocytophilum, Pseudomonas aeruginosa, Chlamydia trachomatis, Mycobacterium tuberculosis) (Bauer et al, 2009;Bruns et al, 2012;Elwell et al, 2008;Jayaswal et al, 2010;Lin et al, 2007;Ly and Casanova, 2009;Muller, 2012;Napier et al, 2011;Pielage et al, 2008;Poppe et al, 2007;Swimm et al, 2004;Tammer et al, 2007) and viruses [vaccinia virus,coxsackievirus,enterovirus 71 (EV71), HIV, hepatitis C virus (HCV) and Ebola virus] (Chen et al, 2007;Coyne and Bergelson, 2006;Garcia et al, 2012;Harmon et al, 2010;Newsome et al, 2006;Reeves et al, 2005;Yamauchi et al, 2015). Microbial pathogens exploit the ability of Abl kinases to regulate cytoskeletal processes in order to achieve efficient internalization, intracellular motility, pedestal formation, cell-to-cell spread, membrane modeling and release (egress).…”

Type IV Secretion and Signal Transduction of Helicobacter pylori CagA through Interactions with Host Cell Receptors

“…However, a crucial mechanism controlling EGFR activity in healthy epithelial cells is ligand-triggered endocytosis, where the internalized receptor recycles back to the plasma membrane or is targeted for degradation [88,89]. Remarkably, while the early H. pylori -mediated transactivation of EGFR is independent of CagA [81,82,83], translocated CagA was required for inhibiting EGFR endocytosis and subsequent degradation during prolonged infections [90]. Activated c-Abl kinase was also essential and induced the upregulation of EGFR surface expression in infected cells through the phosphorylation of EGFR at Y-1173.…”

RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR

“…These closely related non-receptor tyrosine kinases regulate actin remodeling through phosphorylation of actin-associated proteins and through direct F-actin binding (Colicelli, 2010). Although previous studies have implicated ABL proteins in promoting EGFR phosphorylation (Bauer et al, 2009;Plattner et al, 1999;Srinivasan et al, 2008) and actin remodeling has been demonstrated in specialized cases of mammalian cell endocytosis (Boulant et al, 2011), there is no clear mechanism connecting EGF stimulation of EGFR to the activation of ABL and actin remodeling.…”