Helicobacter exploits integrin for type IV secretion and kinase activation.
Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin alpha5beta1 receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori-induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling.
Kwok
Terry
T
Department of Medical Microbiology, Otto von Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany.
Zabler
Dana
D
Urman
Sylwia
S
Rohde
Manfred
M
Hartig
Roland
R
Wessler
Silja
S
Misselwitz
Rolf
R
Berger
Jürgen
J
Sewald
Norbert
N
König
Wolfgang
W
Backert
Steffen
S
D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D010861:Fimbriae, Bacterial / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism* / Q000472:pathogenicity; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D039081:Integrin alpha5beta1; D009842:Oligopeptides; C080866:cagA protein, Helicobacter pylori; C047981:arginyl-glycyl-aspartic acid; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)