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

Stefanie Voigt,Kai R Sterz,Anne-Wiebe Mohr,Andreas Moosmann,Fabian Giehler,Joanna B Wilson,Arnd Kieser

doi:10.1038/s41467-020-14502-x

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.

Highlights

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, and in cancer
TRAF3 extinction is an early step in the activation of the noncanonical NF-κB pathway, which is triggered at CTAR11,30
mouse embryonic fibroblasts (MEFs) expressing NGFR-latent membrane protein 1 (LMP1) constitute a suitable system to study immediate CTAR2 signaling events leading to NF-κB and Jun N-terminal kinase (JNK) activation

Summary

Introduction

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, and in cancer. 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). 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 qualifies as a target for treatment of EBV-induced cancer. TRAF6 and the TNFR-associated death domain protein (TRADD) to activate canonical NF-κB and JNK as the primary readouts of this subdomain[14,15,16,17,18,19] Both CTAR2-induced pathways are required for proliferation and survival of EBV-transformed B cells[20,21].

Methods

Results

Conclusion