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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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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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