Serine/threonine acetylation of TGF -activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling

Division of Infectious Disease, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2012; 109(31):12710-5. DOI: 10.1073/pnas.1008203109
Source: PubMed

ABSTRACT 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.

1 Follower
33 Reads
  • Source
    • "This acetylation reaction results in the inability of upstream kinases to transphosphorylate the downstream kinase, thus preventing the MAPK-mediated cytokine transcriptional response to Yersinia infection (Mukherjee et al., 2006, 2008). Importantly, there is now good evidence that YopJ targets several MAP kinases, including MAPK1, MAPK3, MAPK4, and MAPK5 and TGF-b-activated kinase 1 (TAK1) (Figure 1) (Mukherjee et al., 2006; Paquette et al., 2012). It is also important to note that this general catalytic mechanism has been evolved for specific pathogen purposes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The innate immune system has evolved under selective pressure since the radiation of multicellular life approximately 600 million years ago. Because of this long history, innate immune mechanisms found in modern eukaryotic organisms today are highly complex but yet built from common molecular strategies. It is now clear that evolution has selected a conserved set of antimicrobial peptides as well as pattern-recognition receptors (PRRs) that initiate cellular-based signals as a first line of defense against invading pathogens. Conversely, microbial pathogens employ their own strategies in order to evade, inhibit, or otherwise manipulate the innate immune response. Here, we discuss recent discoveries that have changed our view of immune modulatory mechanisms employed by bacterial pathogens, focusing specifically on the initial sites of microbial recognition and extending to host cellular signal transduction, proinflammatory cytokine production, and alteration of protein trafficking and secretion.
    Molecular cell 04/2014; 54(2):321-328. DOI:10.1016/j.molcel.2014.03.010 · 14.02 Impact Factor
  • Source
    • "Despite an earlier study demonstrating rYopJ activation of TLR-2 signaling in macrophages (Pandey and Sodhi, 2011), in vivo studies employing both Drosophila and macrophage models of infection clearly demonstrated that native YopJ indeed activated the NF-κB signaling but not the TLR-2 signaling pathway (Paquette et al., 2012). It was proposed that following acetylation of key serine/threonine residues in the active sites of both RIP (receptor interacting protein 1)-like interacting caspase-like apoptosis regulatory protein kinase (RICK) and TAK1, YopJ prevented the interaction of RICK and Nod2, a NACHT-leucine-rich repeats (NLRs) recognition receptors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Like other pathogenic bacteria, Yersinia and Aeromonas species have been continuously co-evolving with their respective hosts. Although the former is a bonafide human pathogen, the latter has gained notararity as an emerging disease-causing agent. In response to immune cell challenges, bacterial pathogens have developed diverse mechanism(s) enabling their survival, and, at times, dominance over various host immune defense systems. The bacterial type three secretion system (T3SS) is evolutionarily derived from flagellar subunits and serves as a vehicle by which microbes can directly inject/translocate anti-host factors/effector proteins into targeted host immune cells. A large number of Gram-negative bacterial pathogens possess a T3SS empowering them to disrupt host cell signaling, actin cytoskeleton re-arrangements, and even to induce host-cell apoptotic and pyroptotic pathways. All pathogenic yersiniae and most Aeromonas species possess a T3SS, but they also possess T2- and T6-secreted toxins/effector proteins. This review will focus on the mechanisms by which the T3SS effectors Yersinia outer membrane protein J (YopJ) and an Aeromonas hydrophila AexU protein, isolated from the diarrheal isolate SSU, mollify host immune system defenses. Additionally, the mechanisms that are associated with host cell apoptosis/pyroptosis by Aeromonas T2SS secreted Act, a cytotoxic enterotoxin, and Hemolysin co-regulated protein (Hcp), an A. hydrophila T6SS effector, will also be discussed.
    Frontiers in Cellular and Infection Microbiology 10/2013; 3:70. DOI:10.3389/fcimb.2013.00070 · 3.72 Impact Factor
  • Source
    • "Forty-eight hours later, cells were split 1:2 and then 24 hr thereafter, infected for 90 min with the indicated bacterial strain. FLAG-TAK1 was then immunoprecipitated and used in cold in vitro kinase reactions with recombinant HIS-tagged MKK6-K82A, as previously described by Paquette et al. (2012). Kinase assays were subject to SDS-PAGE, and western blots were probed for pTAK1 and pMKK6, and reprobed with anti-FLAG (Sigma-Aldrich M2 antibody) for total TAK1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vibrio parahaemolyticus type III secretion system 2 (T3SS2) is essential for the organism's virulence, but the effectors required for intestinal colonization and induction of diarrhea by this pathogen have not been identified. Here, we identify a type III secretion system (T3SS2)-secreted effector, VopZ, that is essential for V. parahaemolyticus pathogenicity. VopZ plays distinct, genetically separable roles in enabling intestinal colonization and diarrheagenesis. Truncation of VopZ prevents V. parahaemolyticus colonization, whereas deletion of VopZ amino acids 38-62 abrogates V. parahaemolyticus-induced diarrhea and intestinal pathology but does not impair colonization. VopZ inhibits activation of the kinase TAK1 and thereby prevents the activation of MAPK and NF-κB signaling pathways, which lie downstream. In contrast, the VopZ internal deletion mutant cannot counter the activation of pathways regulated by TAK1. Collectively, our findings suggest that VopZ's inhibition of TAK1 is critical for V. parahaemolyticus to induce diarrhea and intestinal pathology.
    Cell Reports 04/2013; 3(5). DOI:10.1016/j.celrep.2013.03.039 · 8.36 Impact Factor
Show more