YopH prevents monocyte chemoattractant protein 1 expression in macrophages and T-cell proliferation through inactivation of the phosphatidylinositol 3-kinase pathway.
Phosphatidylinositol 3-kinase (PI 3-kinase) and its target protein kinase B (Akt) are involved in various processes including internalization, chemotaxis and proliferation. We analysed the activation of Akt in J774 macrophages infected with virulent (pYV+) or avirulent (pYV-) Yersinia enterocolitica. During the early stage of infection with pYV+ and pYV- bacteria, Akt and its targets, glycogen synthase kinase 3 (GSK-3) and forkhead transcription factor (FKHRL1), became phosphorylated. This phosphorylation induction was inhibited by wortmannin and thus dependent on PI 3-kinase. When infection was carried out with pYV+ bacteria but not with pYV- bacteria, Akt and its targets became dephosphorylated at later time points. Using single knock-out mutants in bacterial effector genes, we have determined that the tyrosine phosphatase YopH was responsible for the inactivation of the PI 3-kinase cascade. In macrophages, this inactivation correlated with the downregulation of mRNA coding for monocyte chemoattractant protein 1 (MCP-1), suggesting that YopH inhibits recruitment of macrophages to lymph nodes. We also analysed the effects of Y. enterocolitica infection on the proliferation of T lymphocytes. Consistent with the observation that YopH inactivated the Akt pathway, YopH inhibited PI 3-kinase-dependent secretion of interleukin 2 and proliferation. These data reveal a new effect of YopH in Yersinia pathogenesis.
Microbial Pathogenesis Unit, Christian de Duve, Institute of Cellular Pathology and Université Catholique de Louvain, Brussels, Belgium.
Nathalie
N
Sauvonnet
Isabelle
I
Lambermont
Pierre
P
van der Bruggen
Guy R
GR
Cornelis
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D014774:Virulence; D000077191:Wortmannin; D015008:Yersinia enterocolitica / Q000737:chemistry*
D000730:Androstadienes; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000077191:Wortmannin; C067571:yopH protein, Yersinia