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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Cliffe, L. J. et al. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308, 1463–1465 (2005)
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)
Iwai, H. et al. A Bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell 130, 611–623 (2007)
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)
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)
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)
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)
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)
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)
Radtke, F. & Clevers, H. Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909 (2005)
Macdonald, T. T. & Monteleone, G. Immunity, inflammation, and allergy in the gut. Science 307, 1920–1925 (2005)
Ogawa, M. & Sasakawa, C. Intracellular survival of Shigella . Cell. Microbiol. 8, 177–184 (2006)
Sansonetti, P. J. War and peace at mucosal surfaces. Nature Rev. Immunol. 4, 953–964 (2004)
Parsot, C. Shigella spp. and enteroinvasive Escherichia coli pathogenicity factors. FEMS Microbiol. Lett. 252, 11–18 (2005)
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)
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)
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)
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)
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)
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)
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)
Lorenz, K. et al. Integrin-linked kinase is required for epidermal and hair follicle morphogenesis. J. Cell Biol. 177, 501–513 (2007)
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)
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)
van der Flier, A. & Sonnenberg, A. Function and interactions of integrins. Cell Tissue Res. 305, 285–298 (2001)
De Arcangelis, A. & Georges-Labouesse, E. Integrin and ECM functions: roles in vertebrate development. Trends Genet. 16, 389–395 (2000)
Kim, M. et al. A new ubiquitin ligase involved in p57KIP2 proteolysis regulates osteoblast cell differentiation. EMBO Rep. 9, 878–884 (2008)
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)
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)
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)
Aszodi, A., Hunziker, E. B., Brakebusch, C. & Fassler, R. Beta1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis. Genes Dev. 17, 2465–2479 (2003)
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)
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)
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)
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)
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)
Ohashi, T. & Erickson, H. P. Domain unfolding plays a role in superfibronectin formation. J. Biol. Chem. 280, 39143–39151 (2005)
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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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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