The germinal center kinase TNIK is required for canonical NF-κB and JNK signaling in B-cells by the EBV oncoprotein LMP1 and the CD40 receptor.
The tumor necrosis factor-receptor-associated factor 2 (TRAF2)- and Nck-interacting kinase (TNIK) is a ubiquitously expressed member of the germinal center kinase family. The TNIK functions in hematopoietic cells and the role of TNIK-TRAF interaction remain largely unknown. By functional proteomics we identified TNIK as interaction partner of the latent membrane protein 1 (LMP1) signalosome in primary human B-cells infected with the Epstein-Barr tumor virus (EBV). RNAi-mediated knockdown proved a critical role for TNIK in canonical NF-κB and c-Jun N-terminal kinase (JNK) activation by the major EBV oncoprotein LMP1 and its cellular counterpart, the B-cell co-stimulatory receptor CD40. Accordingly, TNIK is mandatory for proliferation and survival of EBV-transformed B-cells. TNIK forms an activation-induced complex with the critical signaling mediators TRAF6, TAK1/TAB2, and IKKβ, and mediates signalosome formation at LMP1. TNIK directly binds TRAF6, which bridges TNIK's interaction with the C-terminus of LMP1. Separate TNIK domains are involved in NF-κB and JNK signaling, the N-terminal TNIK kinase domain being essential for IKKβ/NF-κB and the C-terminus for JNK activation. We therefore suggest that TNIK orchestrates the bifurcation of both pathways at the level of the TRAF6-TAK1/TAB2-IKK complex. Our data establish TNIK as a novel key player in TRAF6-dependent JNK and NF-κB signaling and a transducer of activating and transforming signals in human B-cells.
Research Unit Gene Vectors, Helmholtz Zentrum München-German Research Center for Environmental Health, München, Germany.
Anna
A
Shkoda
Jennifer A
JA
Town
Janine
J
Griese
Michael
M
Romio
Hakan
H
Sarioglu
Thomas
T
Knöfel
Fabian
F
Giehler
Arnd
A
Kieser
D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D000081410:Germinal Center Kinases; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000081410:Germinal Center Kinases; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human