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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References
Jung, H.C. et al. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J. Clin. Invest. 95, 55–65 (1995).
Girardin, S.E. et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300, 1584–1587 (2003).
Sansonetti, P.J., Arondel, J., Huerre, M., Harada, A. & Matsushima, K. Interleukin-8 controls bacterial transepithelial translocation at the cost of epithelial destruction in experimental shigellosis. Infect. Immun. 67, 1471–1480 (1999).
Philpott, D.J., Yamaoka, S., Israel, A. & Sansonetti, P.J. Invasive Shigella flexneri activates NF-κB through a lipopolysaccharide-dependent innate intracellular response and leads to IL-8 expression in epithelial cells. J. Immunol. 165, 903–914 (2000).
Kim, D.W. et al. The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc. Natl. Acad. Sci. USA 102, 14046–14051 (2005).
Mukherjee, S. et al. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science 312, 1211–1214 (2006).
Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Thomson, S. et al. The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase. EMBO J. 18, 4779–4793 (1999).
Clayton, A.L., Rose, S., Barratt, M.J. & Mahadevan, L.C. Phosphoacetylation of histone H3 on c-fos- and c-jun-associated nucleosomes upon gene activation. EMBO J. 19, 3714–3726 (2000).
Saccani, S., Pantano, S. & Natoli, G. p38-Dependent marking of inflammatory genes for increased NF-κB recruitment. Nat. Immunol. 3, 69–75 (2002).
Clayton, A.L. & Mahadevan, L.C. MAP kinase-mediated phosphoacetylation of histone H3 and inducible gene regulation. FEBS Lett. 546, 51–58 (2003).
Volmat, V., Camps, M., Arkinstall, S., Pouyssegur, J. & Lenormand, P. The nucleus, a site for signal termination by sequestration and inactivation of p42/p44 MAP kinases. J. Cell Sci. 114, 3433–3443 (2001).
Brondello, J.M., Brunet, A., Pouyssegur, J. & McKenzie, F.R. The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44MAPK cascade. J. Biol. Chem. 272, 1368–1376 (1997).
Menard, R., Sansonetti, P. & Parsot, C. The secretion of the Shigella flexneri Ipa invasins is activated by epithelial cells and controlled by IpaB and IpaD. EMBO J. 13, 5293–5302 (1994).
Mavris, M., Sansonetti, P.J. & Parsot, C. Identification of the cis-acting site involved in activation of promoters regulated by activity of the type III secretion apparatus in Shigella flexneri. J. Bacteriol. 184, 6751–6759 (2002).
Hoffmann, E., Dittrich-Breiholz, O., Holtmann, H. & Kracht, M. Multiple control of interleukin-8 gene expression. J. Leukoc. Biol. 72, 847–855 (2002).
Muegge, K. Preparing the target for the bullet. Nat. Immunol. 3, 16–17 (2002).
Xia, C. et al. Novel sites in the p65 subunit of NF-κB interact with TFIIB to facilitate NF-κB induced transcription. FEBS Lett. 561, 217–222 (2004).
Selsted, M.E., Szklarek, D. & Lehrer, R.I. Purification and antibacterial activity of antimicrobial peptides of rabbit granulocytes. Infect. Immun. 45, 150–154 (1984).
Andersson, K. et al. YopH of Yersinia pseudotuberculosis interrupts early phosphotyrosine signalling associated with phagocytosis. Mol. Microbiol. 20, 1057–1069 (1996).
Fu, Y. & Galan, J.E. The Salmonella typhimurium tyrosine phosphatase SptP is translocated into host cells and disrupts the actin cytoskeleton. Mol. Microbiol. 27, 359–368 (1998).
Espinosa, A., Guo, M., Tam, V.C., Fu, Z.Q. & Alfano, J.R. The Pseudomonas syringae type III-secreted protein HopPtoD2 possesses protein tyrosine phosphatase activity and suppresses programmed cell death in plants. Mol. Microbiol. 49, 377–387 (2003).
Kennelly, P.J. Protein phosphatases–a phylogenetic perspective. Chem. Rev. 101, 2291–2312 (2001).
Zhang, Z.Y. Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. Annu. Rev. Pharmacol. Toxicol. 42, 209–234 (2002).
Natoli, G., Saccani, S., Bosisio, D. & Marazzi, I. Interactions of NF-κB with chromatin: the art of being at the right place at the right time. Nat. Immunol. 6, 439–445 (2005).
Zurawski, D.V., Mitsuhata, C., Mumy, K.L., McCormick, B.A. & Maurelli, A.T. OspF and OspC1 are Shigella flexneri type III secretion system effectors that are required for postinvasion aspects of virulence. Infect. Immun. 74, 5964–5976 (2006).
Alepuz, P.M., Jovanovic, A., Reiser, V. & Ammerer, G. Stress-induced map kinase Hog1 is part of transcription activation complexes. Mol. Cell 7, 767–777 (2001).
Simone, C. et al. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nat. Genet. 36, 738–743 (2004).
Pokholok, D.K., Zeitlinger, J., Hannett, N.M., Reynolds, D.B. & Young, R.A. Activated signal transduction kinases frequently occupy target genes. Science 313, 533–536 (2006).
Wang, Y., Zhang, W., Jin, Y., Johansen, J. & Johansen, K.M. The JIL-1 tandem kinase mediates histone H3 phosphorylation and is required for maintenance of chromatin structure in Drosophila. Cell 105, 433–443 (2001).
Dyson, M.H. et al. MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2. J. Cell Sci. 118, 2247–2259 (2005).
Singer, M. & Sansonetti, P.J. IL-8 is a key chemokine regulating neutrophil recruitment in a new mouse model of Shigella-induced colitis. J. Immunol. 173, 4197–4206 (2004).
Perdomo, O.J. et al. Acute inflammation causes epithelial invasion and mucosal destruction in experimental shigellosis. J. Exp. Med. 180, 1307–1319 (1994).
Perdomo, J.J., Gounon, P. & Sansonetti, P.J. Polymorphonuclear leukocyte transmigration promotes invasion of colonic epithelial monolayer by Shigella flexneri. J. Clin. Invest. 93, 633–643 (1994).
Dieu, M.C. et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188, 373–386 (1998).
Fahy, O.L., Townley, S.L., Coates, N.J., Clark-Lewis, I. & McColl, S.R. Control of Salmonella dissemination in vivo by macrophage inflammatory protein (MIP)-3α/CCL20. Lab. Invest. 84, 1501–1511 (2004).
Harper, J.V. Synchronization of cell populations in G1/S and G2/M phases of the cell cycle. Methods Mol. Biol. 296, 157–166 (2005).
Mateescu, B., England, P., Halgand, F., Yaniv, M. & Muchardt, C. Tethering of HP1 proteins to chromatin is relieved by phosphoacetylation of histone H3. EMBO Rep. 5, 490–496 (2004).
Pedron, T., Thibault, C. & Sansonetti, P.J. The invasive phenotype of Shigella flexneri directs a distinct gene expression pattern in the human intestinal epithelial cell line Caco-2. J. Biol. Chem. 278, 33878–33886 (2003).
Li, C. & Wong, W.H. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl. Acad. Sci. USA 98, 31–36 (2001).
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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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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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)
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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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DOI: https://doi.org/10.1038/ni1423
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