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

Stefanie Voigt, Kai R. Sterz, Fabian Giehler, Anne-Wiebe Mohr, Joanna B. Wilson, Andreas Moosmann and Arnd Kieser ()
Additional contact information
Stefanie Voigt: Research Unit Gene Vectors
Kai R. Sterz: Research Unit Gene Vectors
Fabian Giehler: Research Unit Gene Vectors
Anne-Wiebe Mohr: Research Unit Gene Vectors
Joanna B. Wilson: University of Glasgow
Andreas Moosmann: Research Unit Gene Vectors
Arnd Kieser: Research Unit Gene Vectors

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14502-x

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