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

Abstract

Induction of NF-κB-dependent transcription requires phosphorylation and subsequent degradation of I-κB, an inhibitor of NF-κB, followed by nuclear translocation and DNA binding of NF-κB. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-κB activation in response to cytokines such as tumor necrosis factor α (TNFα). In this study, we purified and characterized a novel kinase (T2K, also known as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activity towards I-κBα in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at ~E14.5 of massive liver degeneration and apoptosis. Nevertheless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNFα-induced apoptosis. In response to either TNFα or IL-1 induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-κB and κB-binding activity. However, NF-κB-directed transcription is dramatically reduced. These results demonstrate that, like I-κB kinase β and the RelA subunit of NF-κB, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF-κB-directed transcription, apparently independent of I-κB degradation and NF-κB DNA binding.