Abstract

Carriage of the CagA oncoprotein by the human gastric cancer-associated pathogen Helicobacter pylori is significantly associated with this typically benign chronic infection advancing to a potentially fatal outcome. However it remains to be elucidated why only a small subset of individuals infected with H. pylori CagA-positive strains develops gastric cancer. H. pylori translocates CagA into host cells using a type IV secretion apparatus that interacts with host integrin receptors via a three-amino-acid-residue RGD motif on the H. pylori protein CagL. The RGD motif of CagL also plays a major role in the induction of proinflammatory responses. Upstream of this motif is a conserved glycine flanked by four hypervariable amino acid residues (residues 58, 59, 61 and 62). Certain amino acid polymorphisms at 58 and 59 are significantly prevalent in strains from gastric cancer patients in particular geographic regions; Y58E59 is seen in Taiwan and D58K59 in India. In light of the seemingly contradictory findings of recent CagL mutagenesis studies, we have examined the contribution of sequence promiscuity specifically at CagL residues 58 and 59 to CagA translocation and H. pylori-mediated proinflammatory responses of gastric epithelial cells. Using isogenic mutants of H. pylori strains P12 and 26695 with amino acid substitutions at CagL residues 58 and 59, we determined that carriage of the polymorphisms Y58E59, D58K59, D58E59, N58E59 or N58K59 did not significantly alter the capacity of H. pylori to translocate CagA into, or induce IL-8 secretion in, host cells. Our findings, together with other recently published data, suggest that the variation at CagL residues 58 and 59 does not influence type IV secretion system function in isolation, but rather may work in concert with particular polymorphisms elsewhere in CagL to modulate disease progression.

Highlights

  • Translocation of the bacterial oncogenic protein CagA into host gastric epithelial cells is an important pathogenic determinant of Helicobacter pylori

  • The amino acid polymorphism combinations examined in this study were: D58K59 and Y58E59 which have both been linked with increased gastric cancer risk [7, 8]; and N58E59, N58K59 and D58E59 which have not shown a specific link to H. pylori disease progression [7,8,9]

  • These various P12 CagL amino acid substitution mutants were co-cultured with AGS gastric epithelial cells and the spent culture media was assayed for IL-8 secretion

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Summary

Introduction

Translocation of the bacterial oncogenic protein CagA into host gastric epithelial cells is an important pathogenic determinant of Helicobacter pylori. CagL triggers host cell spreading [2] and suppresses expression of gastric H,K-ATPase subunit via upregulation of ADAM17 [3]. It is encoded by the 40-kb genetic locus, the cag pathogenicity island (cag PAI), which encodes CagA and other components of the type IV secretion system responsible for CagA translocation [4]. Increased gastric cancer risk has subsequently been reported to associate with the CagL polymorphisms D58K59 in Indian patients [8] and N58 in a Mexican patient cohort [9]. Despite such geographical disparity, understanding the molecular basis for the association of CagL polymorphisms with gastric cancer risk is of great medical interest as it could provide crucial insights into the molecular mechanisms of H. pylori-induced gastric carcinogenesis

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