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Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells

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Abstract

Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55−/− mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC.

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Acknowledgment

This work was supported by grants of the Eberhard-Karls-University of Tübingen (fortüne 1109, IZKF 1459 (Medizinische Fakultät)) to SG and the DFG (AU 102) to IBA.

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Authors and Affiliations

  1. Institute of Medical Microbiology and Hygiene, University of Tübingen, Elfriede-Aulhorn-Str., 6, 72076, Tuebingen, Germany

    Sabine Gröbner, Irena Adkins, Sebastian Schulz, Stefan Borgmann & Ingo B. Autenrieth

  2. Department of Biology, Laboratory of Innate Immunity and Inflammation, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

    Kathleen Richter

  3. Department of Internal Medicine I, University of Tübingen, Tuebingen, Germany

    Sebastian Wesselborg

  4. Institute of Medical Microbiology, University Hamburg-Eppendorf, Hamburg, Germany

    Klaus Ruckdeschel

  5. Inserm, U866, Univ Bourgogne, Dijon, 21079, France

    Olivier Micheau

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  1. Sabine Gröbner
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Gröbner, S., Adkins, I., Schulz, S. et al. Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells. Apoptosis 12, 1813–1825 (2007). https://doi.org/10.1007/s10495-007-0100-x

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