Manifold role of ubiquitin in Helicobacter pylori infection and gastric cancer

Abstract

Infection with H. pylori induces a strong host cellular response represented by induction of a set of molecular signaling pathways, expression of proinflammatory cytokines and changes in proliferation. Chronic infection and inflammation accompanied by secretory dysfunction can result in the development of gastric metaplasia and gastric cancer. Currently, it has been determined that the regulation of many cellular processes involves ubiquitinylation of molecular effectors. The binding of ubiquitin allows the substrate to undergo a change in function, to interact within multimolecular signaling complexes and/or to be degraded. Dysregulation of the ubiquitinylation machinery contributes to several pathologies, including cancer. It is not understood in detail how H. pylori impacts the ubiquitinylation of host substrate proteins. The aim of this review is to summarize the existing literature in this field, with an emphasis on the role of E3 ubiquitin ligases in host cell homeodynamics, gastric pathophysiology and gastric cancer.

Keywords: Bacteria; Cancer; E3 ubiquitin ligases; Inflammation; MDM2; NF-κB; T4SS; p53; β-catenin.

Fig. 1

a Multistep process of ubiquitinylation. The glycine residue at the C-terminus of ubiquitin reacts with an internal cysteine residue of an ubiquitin-activating enzyme (E1) and, in follow, with a cysteine of an ubiquitin-conjugating enzyme (E2). The E2 interacts with an E3 ubiquitin ligase, which facilitates formation of a stable isopeptide bond between the glycine residue at the C-terminus of ubiquitin and a specific internal lysine residue of a substrate protein (1). HECT-type E3 ligases and RING-between-RING (RBR) E3 ubiquitin ligases interact with the E2 enzyme and form a thioester intermediate with ubiquitin before transfer it to a substrate (2). b Types of E3 ubiquitin ligases and composition of a multisubunit cullin-RING ligase. E3 ubiquitin ligases are represented by 3 main groups according to their structure and ability to react with ubiquitin. In the multisubunit RING-type E3s, adaptor proteins can be represented by Skp1 or elongin molecules. SRS substrate recognition subunit, APC/C the anaphase promoting complex/cyclosome, Rbx RING-box protein. The E3 ubiquitin ligases mentioned in the review are depicted

Fig. 2

H. pylori virulence factors have impact on host cell signaling pathways. H. pylori secrete urease, which increases pH in the microenvironment and supports bacterial survival. A set of adhesins allow the bacteria to attach to the host cell surface and to build a T4SS. CagA and, putatively, ADP-heptose are translocated through the T4SS to the cytoplasm and activate SHP2 or ALPK1/TIFA, respectively. ADP-heptose triggers activation of the classical NF-κB pathway. MAP kinases JNK and p38 and the non-classical NF-κB signaling pathway are regulated in a T4SS-dependent but CagA-independent manner (dashed arrows). Bacterial factors responsible for activation of the Akt and MEK/ERK signaling pathways are not known, although an involvement of some adhesins has been discussed. The T4SS and CagA seem to be dispensable for these pathways. H. pylori secrets VacA, which internalizes into host cells, undergoes processing and assembles in stable hexamers that form an ion channel in intracellular membranes. It induces formation of giant vacuoles and, finally, cell death. A serine protease HtrA secreted by H. pylori cleaves E-cadherin and thereby is involved in disruption of adherens junctions and epithelial integrity during infection

Fig. 3

E3 ubiquitin ligases in signaling pathways related to H. pylori infection and gastric cancer (detailed description is in the main text). GFRs growth factor receptors, TNFR TNF receptor, IL1R IL-1β receptor, TLR Toll-like receptor