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


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.

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Available from: Lindsay H Wilson, Jan 08, 2014
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    • "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. "
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    • "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. "
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    • "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. "
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