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Bacteria hijack integrin-linked kinase to stabilize focal adhesions and block cell detachment

Abstract

The rapid turnover and exfoliation of mucosal epithelial cells provides an innate defence system against bacterial infection1,2. Nevertheless, many pathogenic bacteria, including Shigella, are able to surmount exfoliation and colonize the epithelium efficiently3,4. Here we show that the Shigella flexneri effector OspE5,6 (consisting of OspE1 and OspE2 proteins), which is highly conserved among enteropathogenic Escherichia coli, enterohaemorrhagic E. coli, Citrobacter rodentium and Salmonella strains7, reinforces host cell adherence to the basement membrane by interacting with integrin-linked kinase (ILK)8. The number of focal adhesions was augmented along with membrane fraction ILK by ILK–OspE binding. The interaction between ILK and OspE increased cell surface levels of β1 integrin and suppressed phosphorylation of focal adhesion kinase and paxillin, which are required for rapid turnover of focal adhesion in cell motility9. Nocodazole-washout-induced focal adhesion disassembly was blocked by expression of OspE. Polarized epithelial cells infected with a Shigella mutant lacking the ospE gene underwent more rapid cell detachment than cells infected with wild-type Shigella. Infection of guinea pig colons with Shigella corroborated the pivotal role of the OspE–ILK interaction in suppressing epithelial detachment, increasing bacterial cell-to-cell spreading, and promoting bacterial colonization. These results indicate that Shigella sustain their infectious foothold by using special tactics to prevent detachment of infected cells.

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Figure 1: OspE interacts with ILK at focal adhesions.
Figure 2: Interaction between OspE and ILK facilitates FA formation in an ILK kinase domain-dependent manner.
Figure 3: The interaction between OspE and ILK suppresses FA turnover.
Figure 4: Establishment of OspE as a Shigella virulence factor.

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References

  1. Cliffe, L. J. et al. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308, 1463–1465 (2005)

    Article  ADS  CAS  Google Scholar 

  2. Mulvey, M. A., Schilling, J. D., Martinez, J. J. & Hultgren, S. J. Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses. Proc. Natl Acad. Sci. USA 97, 8829–8835 (2000)

    Article  ADS  CAS  Google Scholar 

  3. Iwai, H. et al. A Bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell 130, 611–623 (2007)

    Article  CAS  Google Scholar 

  4. Muenzner, P., Rohde, M., Kneitz, S. & Hauck, C. R. CEACAM engagement by human pathogens enhances cell adhesion and counteracts bacteria-induced detachment of epithelial cells. J. Cell Biol. 170, 825–836 (2005)

    Article  CAS  Google Scholar 

  5. Buchrieser, C. et al. The virulence plasmid pWR100 and the repertoire of proteins secreted by the type III secretion apparatus of Shigella flexneri . Mol. Microbiol. 38, 760–771 (2000)

    Article  CAS  Google Scholar 

  6. Kane, C. D., Schuch, R., Day, W. A. & Maurelli, A. T. MxiE regulates intracellular expression of factors secreted by the Shigella flexneri 2a type III secretion system. J. Bacteriol. 184, 4409–4419 (2002)

    Article  CAS  Google Scholar 

  7. Tobe, T. et al. An extensive repertoire of type III secretion effectors in Escherichia coli O157 and the role of lambdoid phages in their dissemination. Proc. Natl Acad. Sci. USA 103, 14941–14946 (2006)

    Article  ADS  CAS  Google Scholar 

  8. Hannigan, G. E. et al. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 379, 91–96 (1996)

    Article  ADS  CAS  Google Scholar 

  9. Mitra, S. K., Hanson, D. A. & Schlaepfer, D. D. Focal adhesion kinase: in command and control of cell motility. Nature Rev. Mol. Cell Biol. 6, 56–68 (2005)

    Article  CAS  Google Scholar 

  10. Radtke, F. & Clevers, H. Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909 (2005)

    Article  ADS  CAS  Google Scholar 

  11. Macdonald, T. T. & Monteleone, G. Immunity, inflammation, and allergy in the gut. Science 307, 1920–1925 (2005)

    Article  ADS  CAS  Google Scholar 

  12. Ogawa, M. & Sasakawa, C. Intracellular survival of Shigella . Cell. Microbiol. 8, 177–184 (2006)

    Article  CAS  Google Scholar 

  13. Sansonetti, P. J. War and peace at mucosal surfaces. Nature Rev. Immunol. 4, 953–964 (2004)

    Article  CAS  Google Scholar 

  14. Parsot, C. Shigella spp. and enteroinvasive Escherichia coli pathogenicity factors. FEMS Microbiol. Lett. 252, 11–18 (2005)

    Article  CAS  Google Scholar 

  15. Miura, M. et al. OspE2 of Shigella sonnei is required for the maintenance of cell architecture of bacterium-infected cells. Infect. Immun. 74, 2587–2595 (2006)

    Article  CAS  Google Scholar 

  16. Sakai, T. et al. Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation. Genes Dev. 17, 926–940 (2003)

    Article  CAS  Google Scholar 

  17. Lynch, D. K., Ellis, C. A., Edwards, P. A. & Hiles, I. D. Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism. Oncogene 18, 8024–8032 (1999)

    Article  CAS  Google Scholar 

  18. Boulter, E., Grall, D., Cagnol, S. & Van Obberghen-Schilling, E. Regulation of cell-matrix adhesion dynamics and Rac-1 by integrin linked kinase. FASEB J. 20, 1489–1491 (2006)

    Article  CAS  Google Scholar 

  19. Wu, C. & Dedhar, S. Integrin-linked kinase (ILK) and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes. J. Cell Biol. 155, 505–510 (2001)

    Article  CAS  Google Scholar 

  20. Hannigan, G., Troussard, A. A. & Dedhar, S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nature Rev. Cancer 5, 51–63 (2005)

    Article  CAS  Google Scholar 

  21. Legate, K. R., Montanez, E., Kudlacek, O. & Fassler, R. ILK, PINCH and parvin: the tIPP of integrin signalling. Nature Rev. Mol. Cell Biol. 7, 20–31 (2006)

    Article  CAS  Google Scholar 

  22. Lorenz, K. et al. Integrin-linked kinase is required for epidermal and hair follicle morphogenesis. J. Cell Biol. 177, 501–513 (2007)

    Article  CAS  Google Scholar 

  23. Bendig, G. et al. Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart. Genes Dev. 20, 2361–2372 (2006)

    Article  CAS  Google Scholar 

  24. Ezratty, E. J., Partridge, M. A. & Gundersen, G. G. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nature Cell Biol. 7, 581–590 (2005)

    Article  CAS  Google Scholar 

  25. van der Flier, A. & Sonnenberg, A. Function and interactions of integrins. Cell Tissue Res. 305, 285–298 (2001)

    Article  CAS  Google Scholar 

  26. De Arcangelis, A. & Georges-Labouesse, E. Integrin and ECM functions: roles in vertebrate development. Trends Genet. 16, 389–395 (2000)

    Article  CAS  Google Scholar 

  27. Kim, M. et al. A new ubiquitin ligase involved in p57KIP2 proteolysis regulates osteoblast cell differentiation. EMBO Rep. 9, 878–884 (2008)

    Article  CAS  Google Scholar 

  28. Fassler, R. et al. Lack of beta 1 integrin gene in embryonic stem cells affects morphology, adhesion, and migration but not integration into the inner cell mass of blastocysts. J. Cell Biol. 128, 979–988 (1995)

    Article  CAS  Google Scholar 

  29. Shim, D. H. et al. New animal model of shigellosis in the Guinea pig: its usefulness for protective efficacy studies. J. Immunol. 178, 2476–2482 (2007)

    Article  CAS  Google Scholar 

  30. Roberts, M. et al. PDGF-regulated rab4-dependent recycling of αvβ3 integrin from early endosomes is necessary for cell adhesion and spreading. Curr. Biol. 11, 1392–1402 (2001)

    Article  CAS  Google Scholar 

  31. Aszodi, A., Hunziker, E. B., Brakebusch, C. & Fassler, R. Beta1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis. Genes Dev. 17, 2465–2479 (2003)

    Article  CAS  Google Scholar 

  32. Chu, H. et al. gamma-Parvin is dispensable for hematopoiesis, leukocyte trafficking, and T-cell-dependent antibody response. Mol. Cell. Biol. 26, 1817–1825 (2006)

    Article  CAS  Google Scholar 

  33. Sasakawa, C. et al. Molecular alteration of the 140-megadalton plasmid associated with loss of virulence and Congo red binding activity in Shigella flexneri . Infect. Immun. 51, 470–475 (1986)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Datsenko, K. A. & Wanner, B. L. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl Acad. Sci. USA 97, 6640–6645 (2000)

    Article  ADS  CAS  Google Scholar 

  35. Ogawa, M. et al. IcsB, secreted via the type III secretion system, is chaperoned by IpgA and required at the post-invasion stage of Shigella pathogenicity. Mol. Microbiol. 48, 913–931 (2003)

    Article  CAS  Google Scholar 

  36. Cowden Dahl, K. D., Robertson, S. E., Weaver, V. M. & Simon, M. C. Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. Mol. Biol. Cell 16, 1901–1912 (2005)

    Article  CAS  Google Scholar 

  37. Ohashi, T. & Erickson, H. P. Domain unfolding plays a role in superfibronectin formation. J. Biol. Chem. 280, 39143–39151 (2005)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Ohmi, H. Fukuda and C. Takamura for MALDI-TOF analysis. We thank S. Yamaji and Y. Ishigatsubo for discussion. We thank the members of the Sasakawa laboratory, especially H. Mimuro, M. Suzuki and H. Ashida, for their advice. We are grateful to R. Whittier and T. Tezuka for critical reading of the manuscript. We thank H. Erickson for fibronectin fragment expression vector. This work was supported by the Deutsche Forschungsgemeinschaft (SFB576), the Max Planck Society, a Grant-in-Aid for the Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and the Special Coordination Funds for Promoting Science from Japan Science and Technology Agency (JSTA).

Author Contributions M.K., M.O. and Y.F. designed and performed the experiments. T.N. and Y.Y. assisted the experiments. R.F. and A.L. gave advice regarding the design of the experiments and provided ILK materials. T.K. and S.N. made antibodies. C.S. and R.F. wrote the paper.

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Correspondence to Chihiro Sasakawa.

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Kim, M., Ogawa, M., Fujita, Y. et al. Bacteria hijack integrin-linked kinase to stabilize focal adhesions and block cell detachment. Nature 459, 578–582 (2009). https://doi.org/10.1038/nature07952

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