Helicobacter pyloriγ-glutamyl transpeptidase: A formidable virulence factor

Table 1 Summary of the effects of Helicobacter pyloriγ-glutamyl transpeptidase on the host and the possible underlying mechanisms involved

Ref.	Study description	Main findings
Peptic ulcer disease
Gong et al[16] (2010)	Comparison of GGT activity between H. pylori isolates from PUD (n = 54) vs NUD (n = 44) patients.	HpGGT is associated with PUD as strains isolated from PUD patients had significantly higher HpGGT activity compared to those from NUD patients (P < 0.001).
Gastric epithelium damage by apoptosis
Shibayama et al[23] (2003)	Identification of apoptosis-inducing factors from H. pylori by testing different purified membrane fractions of the bacteria on AGS cells.	HpGGT is a leading factor in H. pylori-mediated apoptosis induction.
Kim et al[24] (2007)	Determination of the pathway involved in HpGGT-induced apoptosis by analyzing levels of caspase-9, -3, Bax, Bcl-2, Bcl-xL and cytochrome c release in AGS cells upon treatment with recombinant HpGGT.	HpGGT induces apoptosis via a mitochondria-mediated pathway.
Kim et al[25] (2010)	Examination of the effects of recombinant HpGGT on cell cycle progression in AGS cells.	HpGGT induces cell cycle arrest at the G1-S phase transition. (The authors propose this dysregulation enhances apoptosis induction)
Gong et al[16] (2010)	Investigation of the effects of HpGGT-induced H2O2 production on apoptosis. AGS cells were incubated with purified native HpGGT and NAC (H2O2 inhibitor) and the activities of caspase-3, -8 and -9 were measured.	HpGGT-mediated oxidative stress is required for HpGGT-associated apoptosis.
Promotion of inflammation
Busiello et al[36] (2004)	Purification and identification of secreted H. pylori factors involved in the upregulation of COX-2 expression in MKN28 cells.	HpGGT is able to upregulate COX-2 expression and its enzymatic product, prostaglandin E2.
Gong et al[16] (2010)	Determination of the ability of HpGGT to induce IL-8 production in AGS and primary gastric epithelial cells.	Purified native HpGGT activates NF-κB and upregulates IL-8 production in gastric epithelial cells.
Upregulation of heparin-binding epidermal growth factor-like growth factor
Busiello et al[36] (2004)	Investigation of the ability of HpGGT to upregulate HB-EGF expression in MKN28 cells and elucidating the underlying host cellular pathways involved using specific pathway inhibitors.	HpGGT upregulates HB-EGF expression via activation of a phosphatidylinositol-3 kinase and p38 kinase-dependent signalling transduction pathway. Increase in HB-EGF promotes cell survival and proliferation.
Modulation of host immune response
Schmees et al[60] (2007)	Purification and identification of H. pylori factors responsible for inhibition of T cell proliferation.	HpGGT inhibits T cell proliferation by inducing cell cycle arrest in the G1 phase, possibly through the disruption of a Ras-dependent signalling pathway.
Beigier-Bompadre et al[61] (2011)	Characterization of the interdependent effects of VacA, HpGGT and bacterial cholesterol on T cell proliferation using H. pylori and relevant mutants.	HpGGT antiproliferative activity on T cells is modulated by the bacterial cholesterol/cholesterol α-glucoside content.
Fassi Fehri et al[62] (2010)	Identification of H. pylori factors involved in the regulation of miRNAs in T cells using miRNA profiling.	HpGGT works with H. pylori VacA and lipopolysaccharide to upregulate miRNA-155 expression in CCRF-CEM cells. This was dependent on Foxp3 transcription factor and requires activation of the cAMP cascade.
Oertli et al[68] (2013)	Determination of the role of HpGGT and VacA in dendritic cell reprogramming and development of immune tolerance using in vitro and in vivo models.	Both HpGGT and VacA independently interfere with dendritic cell maturation, possibly contributing to dendritic cell tolerization and hence promoting the persistence of H. pylori infection.

cAMP: Cyclic adenosine monophosphate; COX-2: Cyclooxygenase-2; EGFR: Epidermal growth factor receptor; Foxp3: Forkhead box P3; H. pylori: Helicobacter pylori; HB-EGF: Heparin-binding epidermal growth factor-like growth factor; HpGGT: H. pyloriγ-glutamyl transpeptidase; IL-8: Interleukin-8; miRNA: microRNA; NAC: N-acetylcysteine; NF-κB: Nuclear factor-kappa B; NUD: Non-ulcer dyspepsia; PUD: Peptic ulcer disease; VacA: Vacuolating cytotoxin.