Haem oxygenase-1 inhibits phosphorylation of the Helicobacter pylori oncoprotein CagA in gastric epithelial cells.
The cytotoxin-associated gene A protein (CagA) plays a pivotal role in the aetiology of Helicobacter pylori-associated gastric diseases. CagA is injected into the cytoplasm of host cells by a type IV secretion system, and is phosphorylated on tyrosine residues by the host enzyme c-Src. We previously reported that the enzyme haem oxygenase-1 (HO-1) inhibits IL-8 secretion by H. pylori-infected cells. However, the cellular mechanism by which HO-1 regulates the innate immune function of infected cells remains unknown. We now show that nitric oxide and haemin, two inducers of HO-1, decrease the level of phosphorylated CagA (p-CagA) in H. pylori-infected gastric epithelial cells and this is blocked by either pharmacological inhibition of HO-1 or siRNA knockdown of hmox-1. Moreover, forced expression of HO-1 by transfection of a plasmid expressing hmox-1 also results in a strong attenuation of CagA phosphorylation. This occurs through the inhibition of H. pylori-induced c-Src phosphorylation/activation by HO-1. Consequently, H. pylori-induced cytoskeletal rearrangements and activation of the pro-inflammatory response mediated by p-CagA are inhibited in HO-1-expressing cells. These data highlight a mechanism by which the innate immune response of the host can restrict the pathogenicity of H. pylori by attenuating CagA phosphorylation in gastric epithelial cells.
Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Alain P
AP
Gobert
Thomas
T
Verriere
Thibaut
T
de Sablet
Richard M
RM
Peek
Rupesh
R
Chaturvedi
Keith T
KT
Wilson
D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism*; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology*; D016480:Helicobacter pylori / Q000276:immunology* / Q000472:pathogenicity*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D015513:Oncogene Proteins / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015513:Oncogene Proteins; C080866:cagA protein, Helicobacter pylori; D051547:Heme Oxygenase-1