Department of Department of Medicine, Division of Infectious Diseases and Immunology; Proteomics and Mass Spectrometry Facility, Department of Biochemistry and Molecular Pharmacology
Acetylation; Animals; Bacterial Proteins; Drosophila melanogaster; HEK293 Cells; Humans; *Immunity, Innate; MAP Kinase Kinase Kinases; *MAP Kinase Signaling System; NF-kappa B; Plague; Serine O-Acetyltransferase; Yersinia pestis
Immunology and Infectious Disease
The Gram-negative bacteria Yersinia pestis, causative agent of plague, is extremely virulent. One mechanism contributing to Y. pestis virulence is the presence of a type-three secretion system, which injects effector proteins, Yops, directly into immune cells of the infected host. One of these Yop proteins, YopJ, is proapoptotic and inhibits mammalian NF-kappaB and MAP-kinase signal transduction pathways. Although the molecular mechanism remained elusive for some time, recent work has shown that YopJ acts as a serine/threonine acetyl-transferase targeting MAP2 kinases. Using Drosophila as a model system, we find that YopJ inhibits one innate immune NF-kappaB signaling pathway (IMD) but not the other (Toll). In fact, we show YopJ mediated serine/threonine acetylation and inhibition of dTAK1, the critical MAP3 kinase in the IMD pathway. Acetylation of critical serine/threonine residues in the activation loop of Drosophila TAK1 blocks phosphorylation of the protein and subsequent kinase activation. In addition, studies in mammalian cells show similar modification and inhibition of hTAK1. These data present evidence that TAK1 is a target for YopJ-mediated inhibition.
Proceedings of the National Academy of Sciences of the United States of America
Paquette, Nicholas Paul; Conlon, Joseph E.; Sweet, Charles R.; Rus, Florentina; Wilson, Lindsay; Pereira, Andrea J.; Rosadini, Charles V.; Goutagny, Nadege; Weber, Alexander N. R.; Lane, William S.; Shaffer, Scott A.; Maniatis, Stephanie; Fitzgerald, Katherine A.; Stuart, Lynda M.; and Silverman, Neal S., "Serine/threonine acetylation of TGFbeta-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling" (2012). Infectious Diseases and Immunology Publications and Presentations. 144.