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phosphorylation of IκB, YopP/YopJ prevents its degradation and the translocation of NF-κB to the nucleus. The inhibition of NF-κB activation is accompanied by a lack of activation of the mitogen-activated protein (MAP) kinases (MAPKs) c-Jun-N-terminal kinase (JNK), p38, and extracellular signalregulated kinase (ERK) 1 and 2 (58, 63, 64) that is observed upon infection of macrophages by a Yersinia producing YopP/YopJ. Lack of activation of these MAPKs results from the inhibition of the upstream MAPK kinases (MAPKKs) by binding of YopP/YopJ (62).

Last but not least, YopP/YopJ also induces apoptosis in macrophages (65, 66). This apoptosis is accompanied by cleavage of the cytosolic protein BID, the release of cytochrome c, and the cleavage of caspase-3 and -7 (C. Geuijen, W. Declerq, A. Boland, P. Vandenabeele, and G.R.C., unpublished results). The release of cytochrome c and the cleavage of BID can both be inhibited by caspase inhibitors, suggesting that YopP/YopJ interferes with a signaling pathway upstream of the mitochondria (C. Geuijen, W. Declerq, A. Boland, P. Vandenabeele, and G.R.C., unpublished results). The reduction in the release of TNF-α is not simply the consequence of apoptosis, because it occurs even when apoptosis is prevented by inhibiting the activity of caspases (61). On the contrary, apoptosis may result from the loss of the anti-apoptotic factor NF-κB (61); however, this hypothesis still awaits demonstration. It is thus not yet clear whether YopP/YopJ causes apoptosis by activating a death mechanism or by inhibiting an NF-κB-dependent survival mechanism. Interestingly, YopP/YopJ share a high level of similarity with AvrXv and AvrBsT from X. campestris and a protein from the nitrogen-fixing Rhizobium.

Inhibition of Antigen-Specific T and B Lymphocytes Responses. While they colonize and multiply in Peyer's patches or lymph nodes, Yersinia must also encounter lymphocytes. Artificial in vitro systems demonstrated that B and T lymphocytes are indeed targets for Yersinia injections (ref.67; A. P. Boyd and G.R.C., unpublished results). Yao et al. (68) observed that T and B cells transiently exposed to Yersinia were impaired in their ability to be activated by means of their antigen receptors. T cells are inhibited in their ability to produce cytokines, and B cells are unable to up-regulate surface expression of the costimulatory molecule B7.2, in response to antigenic stimulation. This block of activation results from the inhibition of early phosphorylation events (68). Through the analysis of various mutants, YopH appeared to be the main effector involved in these events. Thus YopH not only contributes to the evasion of the innate immune response but it could also incapacitate the host adaptive immune response.

I thank S. Bleves, G. Denecker, and C. Josenhans for a critical reading. Our work on Yersinia is supported by the Belgian Fonds National de la Recherche Scientifique Médicale (Convention 3.4595.97), the Direction Générale de la Recherche Scientifique-Communauté Française de Belgique (Action de Recherche Concertée 99/04–236), and the Interuniversity Poles of Attraction Program–Belgian State, Prime Minister's Office, Federal Office for Scientific, Technical and Cultural Affairs (PAI 4/03).

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