title: The acetyltransferase activity of the bacterial toxin YopJ of Yersinia is activated by eukaryotic host cell inositol hexakisphosphate.
abstract: Plague, one of the most devastating diseases in human history, is caused by the bacterium Yersinia pestis. The bacteria use a syringe-like macromolecular assembly to secrete various toxins directly into the host cells they infect. One such Yersinia outer protein, YopJ, performs the task of dampening innate immune responses in the host by simultaneously inhibiting the MAPK and NFkappaB signaling pathways. YopJ catalyzes the transfer of acetyl groups to serine, threonine, and lysine residues on target proteins. Acetylation of serine and threonine residues prevents them from being phosphorylated thereby preventing the activation of signaling molecules on which they are located. In this study, we describe the requirement of a host-cell factor for full activation of the acetyltransferase activity of YopJ and identify this activating factor to be inositol hexakisphosphate (IP(6)). We extend the applicability of our results to show that IP(6) also stimulates the acetyltransferase activity of AvrA, the YopJ homologue from Salmonella typhimurium. Furthermore, an IP(6)-induced conformational change in AvrA suggests that IP(6) acts as an allosteric activator of enzyme activity. Our results suggest that YopJ-family enzymes are quiescent in the bacterium where they are synthesized, because bacteria lack IP(6); once injected into mammalian cells by the pathogen these toxins bind host cell IP(6), are activated, and deregulate the MAPK and NFkappaB signaling pathways thereby subverting innate immunity.
authors.affiliation: Medical Research Council (MRC), Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. rohit@mrc-lmb.cam.ac.uk
authors.forename: Rohit
authors.initials: R
authors.lastname: Mittal
authors.forename: Sew Yeu
authors.initials: SY
authors.lastname: Peak-Chew
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sade
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Vallis
authors.forename: Harvey T
authors.initials: HT
authors.lastname: McMahon
mesh_terms: D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000494:Allosteric Regulation; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism; D002850:Chromatography, Gel; D002942:Circular Dichroism; D003600:Cytosol / Q000378:metabolism / Q000382:microbiology; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D010833:Phytic Acid / Q000302:isolation & purification / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011487:Protein Conformation; D015007:Yersinia / Q000201:enzymology* / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C109227:YopP protein, Yersinia; D010833:Phytic Acid; D000123:Acetyltransferases; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2