Cancer-related molecular signal transduction during Helicobacter pylori infections
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1 Cancer-related molecular signal transduction during Helicobacter pylori infections Steffen Backert Professor for Cellular Microbiology University College Dublin School of Biomedical and Biomolecular Sciences Ireland 7th Conference on New Frontiers In Microbiology and Infection Villars-sur-Ollon Switzerland, 2-6 Oct 2011
2 Pathophysiological reactions to H. pylori H. pylori Epithelial cells Th1 dominated cytokines IFN, TNF, IL 12 NF B: IL 1, IL 8, IL 6, Rantes + others CoxII, PGE 2 Acid Infiltration of immune cells Cell proliferation Cell death Cell migration ph ROS and others Cell damage & Tissue disruption Telford et al. (1997) Curr.Opin.Immun. 9:498 Dubois & Borèn (2007) Cell.Microbiol. 9: Hatakeyama ( 2008) Curr. Opin. Microbiol. 11: 30.
3 How H. pylori virulence factors can manipulate host cell signalling? 1. Inject effector proteins into host cell cytosol (example: CagA) 2. Expose adhesive proteins at its surface (example: CagL) 3. Secrete proteins into the culture supernatant (example: HtrA)
4 The CagA protein is encoded by a pathogenicity island VacA H. pylori genome 1.6 Mb cag PAI CagA pathogenicity island (40 kb, ca. 32 genes) DR CagA DR Covacci et al. (1999) Science 284: 1328 Montecucco & Rappuoli (2001) Nat. Rev. Miol. Cell Biol. 2: 457 Peek & Blaser (2002) Nat.Rev.Cancer 2:28
5 Virtually all H. pylori strains worldwide encode VacA but differ in the cagpai status Hp Asia2 cagpai + Hp EastAsia1 cagpai +, cagpai - Hp Europe cagpai +, cagpai - Hp Africa1 cagpai + Hp Africa2 cagpai - H. acinonychis cagpai -, vaca pseudogene acquisition of cagpai, > years Linz et al. (2007) Nature 450:15. Eppinger et al. (2006) PLoS Genet. 2: 120. Falush et al. (2003) Science 299: C. jejuni vaca -, cagpai - last common ancestor of -proteobacteria, vaca -, cagpai - > years H. hepaticus vaca -, cagpai - Picture courtesy by Dr. Bodo Linzc
6 The cag pathogenicity island encodes a type IV secretion system VirB VirB1 VirD4 VirB11 VirB10 VirB8 VirB9 VirB7 VirB6 VirB5 VirB4/B3 CagA Covacci et al. (1999) Science 284: 1328 Rieder et al. (2005) Curr. Opin. Microbiol. 8: 67 Backert & Meyer (2006) Curr. Opin. Microbiol. 9: 207
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8 The cag pathogenicity island encodes a type-iv secretion system Immunogold staining with -CagA antibodies Kwok et al. & Backert (2007) Nature 449: VirB VirB1 VirD4 VirB11 VirB10 VirB8 VirB9 VirB7 VirB6 VirB5 VirB4/B3 CagA Covacci et al. (1999) Science 284: 1328 Rieder et al. (2005) Curr. Opin. Microbiol. 8: 67 Backert & Meyer (2006) Curr. Opin. Microbiol. 9: 207
9 Typ IV Secretion Model 5 min CagA 15 min CagA 30 min Backert & Meyer (2006) Curr. Opin. Microbiol. 9: Backert & Selbach (2005) Trends Microbiol. 13: 476
10 Tyrosine phosphorylation of CagA by a host cell kinase: CagA PY mimics a host cell protein Helicobacter CagA NH 2 - TIGR Y Y Y COOH EPIYA motifs A, B, C Backert et al. (2001) Mol. Microbiology 42: 631 Stein et al. (2002) Mol. Microbiology 43: 451 Selbach et al. & Backert (2002) J. Biol. Chem. 277: 6775.
11 Src oncoprotein is the cellular kinase of CagA in vivo and in vitro Helicobacter CagA NH 2 - Y Y Y -COOH Citrobacter Tir NH 2 - Y Y -COOH EPEC Tir NH 2 - Y Y -COOH Chlamydia Tarp NH 2 - YY Y YY Y Y YY -COOH Bartonella Bep NH 2 - Y Y -COOH Anaplasma AnkA NH 2 - Y Y Y -COOH QPEEHIYDEV AAD Tir-E APEEPIYDEV APD Tir-C ASPEPIYATI DDL CagA STTENIYENIY ES Tarp PQAEPLYAQV NKP BepD DEEIY GEFF Src E Backert und Selbach (2005) Trends Microbiol. 13: 476 Infection in vitro Phosphorylation Mr (kda) H. pylori -CagA-PY-972 CagA-Y- P Mr (kda) c-src -CagA-PY-972 CagA-Y- P 130 -CagA CagA 130 -CagA CagA Backert et al. (2001) Mol. Microbiology 42: 631 Selbach et al. (2002) J. Biol. Chem. 277: 6775 Tammer et al. (2007) Gastroenterology 132: 1309
12 H. pylori infection disrupts the epithelial barrier and induces cell motility AGS cells + H. pylori (6 h) EMT: Epithelial Mesenchymal Transition AGS-Zellen + H. pylori wt (6h) Motility ZO-1 E-cadherin Integrins Selbach et al. & Backert (2003) EMBO Journal 22: 515 Tegtmeyer & Backert (2009) CELL Host & Microbe 5: 514
13 Phosphotyrosine: an essential signal in eukaryotic signal transduction Growth factor Plasma membrane Host Cell Schlessinger (2000) Cell
14 Tyrosine-phosphorylated CagA can bind a high number of host cell SH2-domain factors Type IVsecretion Csk Host cell Grb2 Shp2 PI3K Shp1 Helicobacter CagA NH 2 - TIGR Y Y Y -COOH 918 Proposed role in: - inflammation - proliferation - actin-cytoskeleton - cell shape and migration Selbach et al. (2009) Cell Host Microbe 5: Csk Shp1 Grb2 Shp2 RasGAP Shp1 Grb7
15 Mammalian phosphotyrosine signalling: Lock and key principle ensures high specificity 1 phosphotyrosine binds 1 SH2 domain Tyrosine-phosphorylated CagA: operates as highly promiscuous master key or picklock
16 Injected CagA mimics a eukaryotic protein and induces multiple host signal cascades Type IVsecretion c-raf MEK P P ERK Ras Sos Grb2 P Proliferative genes 3 Cell scattering NF- B Y CagA Y CagA 899 Y P 899 Y 918 P 972 P Selbach et al. & Backert (2003) EMBO Journal 22: 515 Brandt et al. & Backert (2005) PNAS USA 102: 9300 Backert & Selbach (2005) Trends Microbiol. 24: 5269 Backert & Meyer (2006) Curr. Opin. Microbiol. 9: 207 Brandt et al. & Backert (2007) FEMS Microbiol. 50: 190 Tammer et al. & Backert (2007) Gastroenterology 132: 1309 Y Y 2 Csk 1 P P Y P 412 Y Src Y inactive Negative Feeback Loop Abl active 466 Y Host cell P Cortactin Arp2/3 Actin dynamics CrkII P
17 How do H. pylori virulence factors manipulate host cell signalling? 1. Inject effector proteins into host cell cytosol (example: CagA) 2. Expose adhesive proteins at its surface (example: CagL) 3. Secrete proteins into the culture supernatant (example: HtrA)
18 Injected CagA mimics a eukaryotic protein and induces multiple host signal cascades EGFR Type IVsecretion 1 CagL Integrin receptor 4 c-raf MEK P P ERK Ras Sos Grb2 P Proliferative genes 3 Cell scattering NF- B Y CagA Y CagA 899 Y P 899 Y 918 P 972 P Selbach et al. & Backert (2003) EMBO Journal 22: 515 Brandt et al. & Backert (2005) PNAS USA 102: 9300 Backert & Selbach (2005) Trends Microbiol. 24: 5269 Backert & Meyer (2006) Curr. Opin. Microbiol. 9: 207 Brandt et al. & Backert (2007) FEMS Microbiol. 50: 190 Tammer et al. & Backert (2007) Gastroenterology 132: 1309 Y Y 2 Csk 1 P P Y P 412 Y Src Y inactive Negative Feeback Loop Abl active 466 Y Host cell P Cortactin Arp2/3 Elongation phenotype CrkII P
19 CagL CagA cag pathogenicity island (40 kb, ca. 32 genes) NH 2 - SP RGD -COOH AGS + P12 CagL wt AGS + P12 CagL RGA 0.5 m
20 CagL CagA cag pathogenicity island (40 kb, ca. 32 genes) NH 2 - SP RGD -COOH CagL -CagA Kwok et al. & Backert (2007) Nature 449: 862
21 BIACORE: CagL binds integrin 5 1 in a RGD-dependent manner Mr (kda) Biacore Coomassie-Staining CagL wt K = 0.09 M RGA K = 0.36 M CagL CagL D D Binding studies using Surface-Plasmon-Resonance in the BIACORE-System
22 CagL CagA cag pathogenicity island (40 kb, ca. 32 genes) NH 2 - SP RGD -COOH CagA-PY-972 CagA-Y- P CagA -CagA -CagL CagA -CagA Kwok et al. (2007) Nature 449: 862 -CagL
23 SEM: Generation of CagL-coated latex beads for binding studies CagL Latex Beads (1 m) Kwok et al. & Backert (2007) Nature 449: 862
24 SEM: CagL binds integrin 5 1 in a RGD-dependent manner CagL -ß1 Integrin Phalloidin CagL-Beads Latex Beads (1 m) 7 m CagL wt CagL wt CagL RGA 1 m 1 m 1 m Kwok et al. & Backert (2007) Nature 449: 862
25 Bacterial mimicry: Does CagL mimic human fibronectin? Coating with fibronectin Trypsinized AGS cells Petri dish
26 Bacterial mimicry: Does CagL mimic human fibronectin? Coating with fibronectin Trypsinized AGS cells Petri dish Cell attachment and spreading
27 CagL induces cell spreading and focal adhesion formation in a RGD-dependent manner Fibronectin CagL wt CagL-RGA CagL wt (denatured) Fibronectin CagL wt BSA
28 Binding of AGS cells to immobilized CagL induces the tyrosine phosphorylation of host cell proteins Mr (kda) 200 Mock 1h 2h 3h CagL wt Her3/ErbB3 -vinculin EGFR FAK, Abl Src -Phosphotyrosine -PY-99 -phosphotyrosine
29 Purification: CagL is a three -helix bundle with a globular domain Mr (kda) Coomassie-Staining CagL 10-3 (deg cm 2 dmol -1 ) CD Spectrum c = 0.44 mg/ml smoothed spectrum -helices: 65% -sheets: 3% -turns: 14% Random coil: 18% Wave length (nm) Collaboration with Gabriel Waksman, London RGD motif RGD motif Front Back
30 Model for the function of the H. pylori type-iv secretion system Signal transduction Host cell Src Integrin 5 1 Abl P P P OM IM H. pylori CagL VirB2 CagA
31 Activation of EGF receptor by H. pylori CagL Gastroenterology (2010) vol. 139:
32 How can H. pylori establish contact with the integrins at the basolateral membrane? Mucus H. pylori OipA Tight junctions VacA NF- B Adherens junctions IL-8 CagA Integrins M Lamina propria Neutrophil Wessler & Backert (2008) Trends Microbiol. 16: 397.
33 Intracellular, intercellular and stromal invasion of gastric mucosa by Helicobacter pylori Intact Tight junctions Necchi et al. (2007) Gastroenterol. 132: 1009.
34 How do H. pylori virulence factors manipulate host cell signalling? 1. Inject effector proteins into host cell cytosol (example: CagA) 2. Expose adhesive proteins at its surface (example: CagL) 3. Secrete proteins into the culture supernatant (example: HtrA)
35 E cadherin cleavage in response to H. pylori MMP3, 7 ADAM10 Hoy et al., 2010, EMBO Rep Picture courtesy by Prof. S. Wessler c
36 H. pylori HtrA cleaves E cadherin in vitro Hoy et al., 2010, EMBO Rep Löwer et al., PloS ONE, 2008 Picture courtesy by Prof. S. Wessler
37 HtrA cleaves E cadherin on the cell surface Hoy et al., 2010, EMBO Rep Picture courtesy by Prof. S. Wessler
38 Design of a small molecule inhibitor HtrA homology model HHI Helicobacter HtrA Inhibitor Hoy et al., 2010, EMBO Rep Löwer et al., 2011, PloS ONE Picture courtesy by Prof. S. Wessler
39 HHI blocks H. pylori mediated E Cadherin cleavage E-cadherin nucleus Hoy et al., 2010, EMBO Rep Picture courtesy by Prof. S. Wessler
40 H. pylori enters the intercellular space after HtrA mediated E Cadherin cleavage β-actin Hp-GFP Hoy et al., 2010, EMBO Rep Picture courtesy by Prof. S. Wessler
41 Summary: How do H. pylori virulence factors manipulate host cell signalling? 1. Inject effector proteins into host cell cytosol (example: CagA) 2. Expose adhesive proteins at its surface (example: CagL) 3. Secrete proteins into the culture supernatant (example: HtrA)
42 University College Dublin Nicole Tegtmeyer Doreen Baumann Eimear depoire Doreen Müller Aisling Sheridan Grace Gannon Fiona Duffy Manja Böhm University Magdeburg Ruth Wittelsberger Roland Hartig Sabine Brandt Peter Malfertheiner Francisco Rivas Traverso University Salzburg Silja Wessler University Zuerich Giesbert Schneider University Bonn Klemens Rottner University Charleston Adam Smolka Funding SPP1150 EU Acknowledgements
Research article. Department of Medicine/Gastroenterology, Medical University of South Carolina, Charleston, South Carolina, USA.
Related Commentary, page 1192 Research article c-src and c-abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains
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