Serine/threonine acetylation of TGFβ-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling.
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-κB 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-κB 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.
Division of Infectious Disease, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Nicholas
N
Paquette
Joseph
J
Conlon
Charles
C
Sweet
Florentina
F
Rus
Lindsay
L
Wilson
Andrea
A
Pereira
Charles V
CV
Rosadini
Nadege
N
Goutagny
Alexander N R
AN
Weber
William S
WS
Lane
Scott A
SA
Shaffer
Stephanie
S
Maniatis
Katherine A
KA
Fitzgerald
Lynda
L
Stuart
Neal
N
Silverman
D000107:Acetylation; D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D020930:MAP Kinase Kinase Kinases / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010930:Plague / Q000276:immunology / Q000378:metabolism; D051050:Serine O-Acetyltransferase / Q000276:immunology / Q000378:metabolism*; D015010:Yersinia pestis / Q000201:enzymology* / Q000276:immunology / Q000472:pathogenicity; D000099151:MAP Kinase Kinase Kinase 7
D001426:Bacterial Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D051050:Serine O-Acetyltransferase; D000099151:MAP Kinase Kinase Kinase 7; C109227:YopP protein, Yersinia