title: A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system.
abstract: The type IV secretion system (T4SS) of Helicobacter pylori triggers massive inflammatory responses during gastric infection by mechanisms that are poorly understood. Here we provide evidence for a novel pathway by which the T4SS structural component, CagL, induces secretion of interleukin-8 (IL-8) independently of CagA translocation and peptidoglycan-sensing nucleotide-binding oligomerization domain 1 (NOD1) signalling. Recombinant CagL was sufficient to trigger IL-8 secretion, requiring activation of α5 β1 integrin and the arginine-glycine-aspartate (RGD) motif in CagL. Mutation of the encoded RGD motif to arginine-glycine-alanine (RGA) in the cagL gene of H. pylori abrogated its ability to induce IL-8. Comparison of IL-8 induction between H. pylori ΔvirD4 strains bearing wild-type or mutant cagL indicates that CagL-dependent IL-8 induction can occur independently of CagA translocation. In line with this notion, exogenous CagL complemented H. pylori ΔcagL mutant in activating NF-κB and inducing IL-8 without restoring CagA translocation. The CagA translocation-independent, CagL-dependent IL-8 induction involved host signalling via integrin α5 β1 , Src kinase, the mitogen-activated protein kinase (MAPK) pathway and NF-κB but was independent of NOD1. Our findings reveal a novel pathway whereby CagL, via interaction with host integrins, can trigger pro-inflammatory responses independently of CagA translocation or NOD1 signalling.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia; Department of Microbiology, Monash University, Clayton, Vic., Australia.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Gorrell
authors.forename: Jyeswei
authors.initials: J
authors.lastname: Guan
authors.forename: Yue
authors.initials: Y
authors.lastname: Xin
authors.forename: Mona Anoushiravani
authors.initials: MA
authors.lastname: Tafreshi
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ferrero
authors.forename: Terry
authors.initials: T
authors.lastname: Kwok
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D058947:Bacterial Secretion Systems; D002460:Cell Line; D016480:Helicobacter pylori / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D039081:Integrin alpha5beta1; D016209:Interleukin-8; D050505:Mutant Proteins; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; C080866:cagA protein, Helicobacter pylori; C568315:cagL protein, Helicobacter pylori