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Manipulation of host Kruppel-like factor (KLF) function by exotoxins from diverse bacterial pathogens

Nature Reviews Microbiology volume 5, pages 337–341 (2007)Cite this article

Key Points

  • Gram-negative and Gram-positive pathogens use a common virulence strategy to increase the expression of Kruppel-like factor mammalian transcriptional regulators.

  • This strategy involves the subversion of host cell functions by secreting bacterial exotoxins using a type III secretion system or an alternative secretion mechanism.

  • Exploitation of the Kruppel-like factor regulatory cascade results in the modulation of numerous cell processes, including NFκB activation, pro-inflammatory cytokine expression, actin cytoskeletal dynamics, cell proliferation and phagocytosis.

  • The modulation of Kruppel-like factors 2 and 6 by diverse pathogens such as Pseudomonas aeruginosa, Yersinia enterocolitica, Clostridium botulinum and Staphylococcus aureus could involve a common mechanism based on altered activities of the Rho protein signalling cascade.

  • Increased expression of KLF2 by bacterial pathogens may be due to relief from repression of KLF2 by Rho-GTP, which may or may not involve NFκB, itself a negative regulator of KLF2 expression.

  • Analysis of the modular structure of the bacterial effector proteins indicates that enzymatic substrate specificity has an important role in the alteration of these transcriptional regulators.

  • Increased expression of Kruppel-like factors 2 and/or 6, as is seen in response to bacterial infection would result in decreased expression of NFκB and JUN, inhibition of phagocytosis, pro-inflammatory cytokines and cellular proliferation, ultimately to the detriment of the host.

Abstract

Diverse pathogenic bacteria have developed similar mechanisms to subvert host cell responses. In this Progress article, we focus on bacterial virulence factors with different enzymatic activities that can increase the expression of the Kruppel-like factor (KLF) family of mammalian transcriptional regulators through their ability to modify the activity of a common host-cell target — the Rho protein family. By using a common virulence strategy, both Gram-negative and Gram-positive pathogens exploit the KLF regulatory cascade to modulate nuclear factor κB activation, pro-inflammatory cytokine expression, actin cytoskeletal dynamics and phagocytosis.

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Figure 1: Microbial pathogens control Kruppel-like factors through regulation of Rho proteins.
Figure 2: Conserved functional domains of secreted bacterial proteins that modulate the expression of KLF2 and KLF6.

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Acknowledgements

This work was supported in part by grants awarded by the Higher Education Authority of Ireland (PRTLI programme), the Science Foundation of Ireland, the European Commission and the Health Research Board.

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Authors and Affiliations

  1. Department of Microbiology, Eoin O'Grady, Heidi Mulcahy, Claire Adams and Fergal O'Gara are at the BIOMERIT Research Centre, University College Cork, Cork, Ireland.,

    Eoin O'Grady, Heidi Mulcahy, Claire Adams & Fergal O'Gara

  2. John Morrissey is at the Department of Microbiology, University College Cork, Cork, Ireland.,

    John P. Morrissey

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DATABASES

Entrez Genome Project

Clostridium botulinum

Escherichia coli

Pseudomonas aeruginosa

Staphylococcus aureus

Yersinia enterocolitica

Yersinia pestis

Yersinia pseudotuberculosis

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O'Grady, E., Mulcahy, H., Adams, C. et al. Manipulation of host Kruppel-like factor (KLF) function by exotoxins from diverse bacterial pathogens. Nat Rev Microbiol 5, 337–341 (2007). https://doi.org/10.1038/nrmicro1641

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