Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach.
Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan into host cells. NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure. We previously demonstrated that the H. pylori cag(+) strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Coculture of H. pylori strain 7.13 or its pgdA(-) isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA(-) mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, preactivation of NOD1 before bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared with noncancer samples harvested from the same patients. These results indicate that peptidoglycan deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.
Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee.
Giovanni
G
Suarez
Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee.
Judith
J
Romero-Gallo
Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee.
M Blanca
MB
Piazuelo
Department of Microbiology, University of Georgia, Athens, Georgia.
Ge
G
Wang
Department of Microbiology, University of Georgia, Athens, Georgia.
Robert J
RJ
Maier
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia.
Lennart S
LS
Forsberg
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia.
Parastoo
P
Azadi
Department of Medicine, National University of Colombia, Bogota, Colombia. Hospital El Tunal Unit of Gastroenterology, Bogota, Colombia.
Martin A
MA
Gomez
Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee.
Pelayo
P
Correa
Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee. richard.peek@vanderbilt.edu.
Richard M
RM
Peek
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology*; D000368:Aged; D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005756:Gastritis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D020868:Gene Silencing; D005849:Gerbillinae; D057809:HEK293 Cells; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D030781:Organisms, Genetically Modified; D010457:Peptidoglycan / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology*
D001426:Bacterial Proteins; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; D000123:Acetyltransferases; D000581:Amidohydrolases