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A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation

Author

Listed:
  • Stefanie Voigt

    (Research Unit Gene Vectors)

  • Kai R. Sterz

    (Research Unit Gene Vectors)

  • Fabian Giehler

    (Research Unit Gene Vectors
    German Centre for Infection Research (DZIF), Partner Site Munich)

  • Anne-Wiebe Mohr

    (Research Unit Gene Vectors
    German Centre for Infection Research (DZIF), Partner Site Munich)

  • Joanna B. Wilson

    (University of Glasgow)

  • Andreas Moosmann

    (Research Unit Gene Vectors
    German Centre for Infection Research (DZIF), Partner Site Munich
    Ludwig-Maximilians-University Munich, Grosshadern)

  • Arnd Kieser

    (Research Unit Gene Vectors
    German Centre for Infection Research (DZIF), Partner Site Munich)

Abstract

IκB kinase 2 (IKK2) is well known for its pivotal role as a mediator of the canonical NF-κB pathway, which has important functions in inflammation and immunity, but also in cancer. Here we identify a novel and critical function of IKK2 and its co-factor NEMO in the activation of oncogenic c-Jun N-terminal kinase (JNK) signaling, induced by the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). Independent of its kinase activity, the TGFβ-activated kinase 1 (TAK1) mediates LMP1 signaling complex formation, NEMO ubiquitination and subsequent IKK2 activation. The tumor progression locus 2 (TPL2) kinase is induced by LMP1 via IKK2 and transmits JNK activation signals downstream of IKK2. The IKK2-TPL2-JNK axis is specific for LMP1 and differs from TNFα, Interleukin−1 and CD40 signaling. This pathway mediates essential LMP1 survival signals in EBV-transformed human B cells and post-transplant lymphoma, and thus qualifies as a target for treatment of EBV-induced cancer.

Suggested Citation

  • Stefanie Voigt & Kai R. Sterz & Fabian Giehler & Anne-Wiebe Mohr & Joanna B. Wilson & Andreas Moosmann & Arnd Kieser, 2020. "A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14502-x
    DOI: 10.1038/s41467-020-14502-x
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    Cited by:

    1. Fabian Giehler & Michael S. Ostertag & Thomas Sommermann & Daniel Weidl & Kai R. Sterz & Helmut Kutz & Andreas Moosmann & Stephan M. Feller & Arie Geerlof & Brigitte Biesinger & Grzegorz M. Popowicz &, 2024. "Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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