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An injected bacterial effector targets chromatin access for transcription factor NF-κB to alter transcription of host genes involved in immune responses

Nature Immunology volume 8, pages 47–56 (2007)Cite this article

Abstract

Phosphorylation of histone H3 at Ser10 increases chromatin accessibility to transcription factor NF-κB on a subset of genes involved in immune responses. Here we report that a bacterial pathogen abrogated phosphorylation of histone H3 to 'shape' the transcriptional responses of infected host cells. We identify the Shigella flexneri protein effector OspF as a dually specific phosphatase that dephosphorylated mitogen-activated protein kinases in the nucleus, thus preventing histone H3 phosphorylation at Ser10 in a gene-specific way. That activity of OspF enabled shigella to block the activation of a subset of NF-κB-responsive genes, leading to compromised recruitment of polymorphonuclear leukocytes to infected tissues. S. flexneri has thus evolved the capacity to precisely modulate host cell epigenetic 'information' as a strategy for repressing innate immunity.

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Figure 1: Shigella inactivates Erk in the nucleus.
Figure 2: OspF is a DSP.
Figure 3: OspF is selective for the inactivation of Erk and p38.
Figure 4: OspF localizes to the nucleus of shigella-infected cells.
Figure 5: OspF represses a subset of genes involved in the immune response.
Figure 6: OspF targets H3pS10 in a MAPK-dependent way.
Figure 7: OspF impairs the formation of histone H3–phosphorylated promoters in a gene-selective way.
Figure 8: OspF represses polymorphonuclear leukocyte recruitment and restricts bacterial invasion of shigella-infected tissues.

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Acknowledgements

We thank R. Weil and S. Memet for critical reading of the manuscript; J. Rohde, C. Rougeot, L. Touqui and A. Garcia for discussions; and B. Regnault and J. Bergounioux for technical assistance. The pGEX 2T plasmid containing human Erk2 was a gift from C. Marshall (Institute of Cancer Research); antibody to histone H3 methylated at Lys9 and phosphorylated at Ser10 was a gift from C. Muchardt (Institut Pasteur); and anti-p50 and anti-p65 were gifts from R. Weil (Institut Pasteur). Supported by the Howard Hughes Medical Institute (P.J.S.).

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Author notes

  1. Dong Wook Kim

    Present address: Molecular Genetics section, International Vaccine Institute, SNU Research Park, San 4-8, Bongcheon-7-dong, Kwanak-gu, Seoul, 151-818, Korea

Authors and Affiliations

  1. Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, F75724, Cedex 15, France

    Laurence Arbibe, Dong Wook Kim, Thierry Pedron, Claude Parsot & Philippe J Sansonetti

  2. Institut National de la Santé et de la Recherche Médicale, U786, Paris, F75724, Cedex 15, France

    Laurence Arbibe, Dong Wook Kim, Thierry Pedron, Claude Parsot & Philippe J Sansonetti

  3. Département de Biologie du Développement, Expression Génétique et Maladie, URA1644 du Centre National de la Recherche Scientifique, Institut Pasteur, Paris, 75015, France

    Eric Batsche, Bogdan Mateescu & Christian Muchardt

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Contributions

All authors contributed to discussions and manuscript criticism; L.A. designed and did most of the experiments and wrote the manuscript; D.W.K. and C.P. provided the ospF mutant and the trans-complemented strains, the E. coli strain containing pGEX4T2-OspF, the OspG and IpaH proteins, and polyclonal antibody to OspF; E.B. did mathematical analysis of the quantitative PCR data; T.P. did the microarrray and immunolabeling experiments; B.M. examined the effect of OspF on purified histones; B.M. and C.M. produced and characterized the antibody to histone H3 methylated at Lys9 and phosphorylated at Ser10; and P.J.S. did the in vivo rabbit infection experiments and the histological data analysis.

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Correspondence to Laurence Arbibe.

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Supplementary information

Supplementary Fig. 1

OspF homology with other putative virulence proteins. (PDF 629 kb)

Supplementary Fig. 2

Dephosphorylation of the 33P-labeled Erk2 by OspF and MKP1. (PDF 126 kb)

Supplementary Fig. 3

Hierarchical clustering of the OspF-modulated genes. (PDF 684 kb)

Supplementary Fig. 4

OspF does not directly dephosphorylate histone H3 at serine 10. (PDF 157 kb)

Supplementary Fig. 5

SDS-PAGE analysis of purified GST-OspF. (PDF 744 kb)

Supplementary Methods (PDF 43 kb)

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Arbibe, L., Kim, D., Batsche, E. et al. An injected bacterial effector targets chromatin access for transcription factor NF-κB to alter transcription of host genes involved in immune responses. Nat Immunol 8, 47–56 (2007). https://doi.org/10.1038/ni1423

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