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. © 2012 shkoda et al.