Helicobacter pylori CagA induces AGS cell elongation through a cell retraction defect that is independent of Cdc42, Rac1, and Arp2/3.
Helicobacter pylori, which infects over one-half the world's population, is a significant risk factor in a spectrum of gastric diseases, including peptic ulcers and gastric cancer. Strains of H. pylori that deliver the effector molecule CagA into host cells via a type IV secretion system are associated with more severe disease outcomes. In a tissue culture model of infection, CagA delivery results in a dramatic cellular elongation referred to as the "hummingbird" phenotype, which is characterized by long, thin cellular extensions. These actin-based cytoskeletal rearrangements are reminiscent of structures that are regulated by Rho GTPases and the Arp2/3 complex. We tested whether these signaling pathways were important in the H. pylori-induced cell elongation phenotype. Contrary to our expectations, we found that these molecules are dispensable for cell elongation. Instead, time-lapse video microscopy revealed that cells infected by cagA(+) H. pylori become elongated because they fail to release their back ends during cell locomotion. Consistent with a model in which CagA causes cell elongation by inhibiting the disassembly of adhesive cell contacts at migrating cells' lagging ends, immunohistochemical analysis revealed that focal adhesion complexes persist at the distal tips of elongated cell projections. Thus, our data implicate a set of signaling molecules in the hummingbird phenotype that are different than the molecules previously suspected.
Bourzac
Kevin M
KM
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Botham
Crystal M
CM
Guillemin
Karen
K
D051377:Actin-Related Protein 2 / Q000502:physiology*; D051378:Actin-Related Protein 3 / Q000502:physiology*; D000942:Antigens, Bacterial / Q000502:physiology*; D001426:Bacterial Proteins / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D045744:Cell Line, Tumor; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D010641:Phenotype; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
C495926:ACTR2 protein, human; C495928:ACTR3 protein, human; D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C107953:RAC1 protein, human; C080866:cagA protein, Helicobacter pylori; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein