Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappa B-dependent gene transcription

induction of NF-kappa B-dependent transcription requires phosphorylation an d subsequent degradation of I-kappa B, an inhibitor of NF-kappa B, followed by nuclear translocation and DNA binding of NF-kappa B. Tumor necrosis fac tor receptor-associated factor 2 (TRAF2) plays a role in NF-kappa B activat ion in response to cytokines such as tumor necrosis factor alpha (TNF alpha ). In this study, we purified and characterized a novel kinase (T2K, also k nown as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activ ity towards I-kappa B alpha in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2 k(-/-) animals die at similar to E14.5 of massive liver degeneration and ap optosis, Nevertheless, hematopoietic progenitors from T2K-deficient fetal l iver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNF alp ha-induced apoptosis. In response to either TNF alpha or IL-1, induction, t 2k(-/-) embryonic fibroblasts exhibit normal degradation of I-kappa B and k appa B-binding activity. However, NF-kappa B-directed transcription is dram atically reduced. These results demonstrate that, like I-kappa B kinase bet a and the ReIA subunit of NF-kappa B, T2K is critical in protecting embryon ic liver from apoptosis, However, T2K has a unique role in the activation o f NF-kappa B-directed transcription, apparently independent of I-kappa B de gradation and NF-kappa B DNA binding.