<i>Yersinia</i> Outer Protein P of <i>Yersinia enterocolitica</i> Simultaneously Blocks the Nuclear Factor-κB Pathway and Exploits Lipopolysaccharide Signaling to Trigger Apoptosis in Macrophages

Ruckdeschel, Klaus; Mannel, Oliver; Richter, Kathleen; Jacobi, Christoph A.; Trülzsch, Konrad; Rouot, Bruno; Heesemann, Jürgen

doi:10.4049/jimmunol.166.3.1823

Cited by 142 publications

(199 citation statements)

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“…Orth et al (1999) made the key observation that YopJ can bind to multiple members of the MAPK kinase superfamily, including MKKs and IKKb, and suppress their activation. The interaction between YopJ and IKKb was also confirmed by co-immunoprecipitation from macrophages (Denecker et al, 2001;Ruckdeschel et al, 2001).…”

Section: Yopjmentioning

confidence: 65%

Yersinia effectors target mammalian signalling pathways

2002

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SummaryAnimals have an immune system to fight off challenges from both viruses and bacteria. The first line of defence is innate immunity, which is composed of cells that engulf pathogens as well as cells that release potent signalling molecules to activate an inflammatory response and the adaptive immune system. Pathogenic bacteria have evolved a set of weapons, or effectors, to ensure survival in the host. Yersinia spp. use a type III secretion system to translocate these effector proteins, called Yops, into the host. This report outlines how Yops thwart the signalling machinery of the host immune system. Introduction Innate immunity and signallingInnate immunity is the first line of defence against bacterial and viral infection (for a review of innate immunity, see Medzhitov and Janeway, 2000). The cells involved in the immune response use a wide variety of signalling cascades to activate processes such as phagocytosis, cytokine production and release and production of reactive oxygen species. In addition to eliminating pathogens, the innate immune system activates the adaptive immune response through the presentation of foreign peptides to T cells.Phagocytosis is an essential component of the innate immune system (May and Machesky, 2001). Rearrangement of the actin cytoskeleton during phagocytosis is mediated by the recruitment of proteins that function in actin rearrangement; these include paxillin, p130Cas and focal adhesion kinase (FAK) (Greenberg et al., 1990;Allen and Aderem, 1996). These proteins may form through M cells (microfold cells), which are specialized cells that take up foreign antigens, in intestinal Peyer's patches (Autenrieth and Firsching, 1996). Recognition of Yersinia by M cells is mediated via b1 integrins on the M-cell plasma membrane and the invasin protein of Yersinia (Marra and Isberg, 1997;Clark et al., 1998). Once Yersinia has penetrated the M cells, it can localize in the lymphoid tissue of its host.The recently sequenced genome of Y. pestis (Parkhill et al., 2001) suggests that many of the genes that Yersinia uses during infection and invasion, including adhesins, secretion systems and insecticidal toxins, have been acquired from other bacteria and viruses. Furthermore, all three pathogenic species of Yersinia harbour an extrachromosomal plasmid of 70 kb that is essential for virulence (Portnoy and Martinez, 1985). This plasmid contains the genes of a type III secretion system, a translocation apparatus highly conserved among pathogenic Gram-negative bacteria (for a review, see Cornelis, 1998). This secretion system is responsible for the translocation of the Yersinia effectors, termed Yops, into the host cell. Once inside the host cell, Yops carry out disruption of signalling cascades that activate the processes of phagocytosis, cytokine release and respiratory burst. Six Yop effectors have been identified (YopH, YopE, YopJ/P, YpkA/YopO, YopT and YopM). Some of these effectors are known to function in the downregulation of critical signalling cascades of the immune system (Fig...

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Section: Yopjmentioning

confidence: 65%

Yersinia effectors target mammalian signalling pathways

2002

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“…Twenty-four hours after transfection, HEK293 cells were serum-starved for 18 -20 h, then stimulated as indicated. J774A.1 cells were transfected with 0.33 g of pSV-␤-galactosidase expression vector and 0.66 g of the plasmid of interest (16). Three hours after transfection, J774A.1 cells were treated with MG-132 and stimulated 30 min later.…”

Section: Analysis Of Morphology Of Transfected Cellsmentioning

confidence: 99%

“…To identify the transfected cells, the cells were fixed and stained with 5-bromo-4-chloro-3-indolyl ␤-D-galactoside (X-gal) at the time points indicated. For assessment of cell death, the morphology of blue transfected cells was determined using light microscopy (7)(8)(9)(10)16). Every single transfected cell was analyzed for an apoptotic appearance.…”

Section: Analysis Of Morphology Of Transfected Cellsmentioning

confidence: 99%

“…YopP/YopJ is injected by the virulence plasmid-encoded Yersinia type III protein secretion system into the host cell cytoplasm where it binds and inhibits the NF-B-activating inhibitory B kinase (IKK)-␤, leading to down-regulation of NF-B activation (14,15). Our previous studies have shown that proapoptotic signals of innate immunity could synergize with the NF-B-inhibitory action of YopP/YopJ to mediate macrophage apoptosis (16). This suggests that yersiniae activate a conserved apoptotic pathway that induces cell death when NF-B activation is suppressed.…”

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confidence: 99%

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A Dominant Role of Toll-Like Receptor 4 in the Signaling of Apoptosis in Bacteria-Faced Macrophages

Haase

Kirschning

Sing

et al. 2003

The Journal of Immunology

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121

129

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Conserved bacterial components potently activate host immune cells through transmembrane Toll-like receptors (TLRs), which trigger a protective immune response but also may signal apoptosis. In this study, we investigated the roles of TLR2 and TLR4 as inducers of apoptosis in Yersinia enterocolitica-infected macrophages. Yersiniae suppress activation of the antiapoptotic NF-κB signaling pathway in host cells by inhibiting inhibitory κB kinase-β. This leads to macrophage apoptosis under infection conditions. Experiments with mouse macrophages deficient for TLR2, TLR4, or both receptors showed that, although yersiniae could activate signaling through both TLR2 and TLR4, loss of TLR4 solely diminished Yersinia-induced apoptosis. This suggests implication of TLR4, but not of TLR2, as a proapoptotic signal transducer in Yersinia-conferred cell death. In the same manner, agonist-specific activation of TLR4 efficiently mediated macrophage apoptosis in the presence of the proteasome inhibitor MG-132, an effect that was less pronounced for activation through TLR2. Furthermore, the extended stimulation of overexpressed TLR4 elicited cellular death in epithelial cells. A dominant-negative mutant of Fas-associated death domain protein could suppress TLR4-mediated cell death, which indicates that TLR4 may signal apoptosis through a Fas-associated death domain protein-dependent pathway. Together, these data show that TLR4 could act as a potent inducer of apoptosis in macrophages that encounter a bacterial pathogen.

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“…For example, LPS was reported to cause cell death of conA or IFN-γ primed macrophages and to enhance cell death induced by the Yersinia baccillus [17,20,21]. Intriguingly, it was found that zVAD and boc-D, pan-caspase inhibitors that inhibit apoptosis in many different cells, not only had no inhibitory effect on LPS-induced apoptosis in INF-γ primed macrophages but also by themselves induced susceptibility to LPS-induced cell death in macrophages [22].…”

Section: Introductionmentioning

confidence: 99%

MEF2C mediates the activation induced cell death (AICD) of macrophages

Wei

2006

Cell Res

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Activation-induced cell death (AICD) of immune cells is widely believed to be crucial for the regulation of immune responses. Although macrophage apoptosis has been observed under a variety of pathological conditions, questions as to whether there is AICD of macrophages and how macrophage life span is regulated have not been well addressed. AICD in macrophages requires two signals. One is cell activation triggered by LPS or other bacterial components. The other is an event that exists in AICD-susceptible (primed) but not unsusceptible (resting) macrophages. Here we show that RAW264.7 cell is susceptible to LPS stimulation when it is primed with Salmonella typhimurium, type 5 adenovirus (Ad5) or IFN-g. We found that the stability of the transcription factor MEF2C is increased in primed RAW264.7 cell. Transfection of a dominant negative form of MEF2C protects primed macrophage from cell death triggered by LPS. Our data demonstrate that the increase of MEF2C protein stability is a key factor in the AICD of macrophage.

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Yersinia Outer Protein P of Yersinia enterocolitica Simultaneously Blocks the Nuclear Factor-κB Pathway and Exploits Lipopolysaccharide Signaling to Trigger Apoptosis in Macrophages

Cited by 142 publications

References 36 publications

Yersinia effectors target mammalian signalling pathways

Yersinia effectors target mammalian signalling pathways

A Dominant Role of Toll-Like Receptor 4 in the Signaling of Apoptosis in Bacteria-Faced Macrophages

MEF2C mediates the activation induced cell death (AICD) of macrophages

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