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

Voigt, S., Sterz, K. R., Giehler, F., Mohr, A.-W., Wilson, J. B. , Moosmann, A. and Kieser, A. (2020) A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation. Nature Communications, 11, 685. (doi: 10.1038/s41467-020-14502-x) (PMID:32019925) (PMCID:PMC7000802)

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.

• Item Type: Articles
• Additional Information: This work was supported by grants Ki 825/1–3 of the German Research Foundation (DFG), e:Med 031A428G by the Federal Ministry of Education and Research, and TTU 07.802 and TTU 07.809 by the German Research Center for Infection Research (DZIF) to A.K.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Wilson, Professor Joanna
• Authors: Voigt, S., Sterz, K. R., Giehler, F., Mohr, A.-W., Wilson, J. B., Moosmann, A., and Kieser, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature Communications 11: 685
• Publisher Policy: Reproduced under a Creative Commons License