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 and 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 factor receptor-associated factor 2 (TRAF2) plays a role in NF-[kappa]B ac...

Full description

Saved in:
Bibliographic Details
Published in:The EMBO journal 2000-09, Vol.19 (18), p.4976-4985
Main Authors: Bonnard, Madeleine, Mirtsos, Christine, Suzuki, Shinobu, Graham, Kevin, Huang, Jianing, Ng, Michelle, Itie, Annick, Wakeham, Andrew, Shahinian, Arda, Henzel, William J, Elia, Andrew J, Shillinglaw, Wendy, Mak, Tak W, Cao, Zhaodan, Wen-Chen, Yeh
Format: Article
Language:English
Subjects:
Deoxyribonucleic acid
DNA
I^KB protein
Liver
Lymphocytes
NF-^KB protein
relA protein
T2K protein
Translocation
tumor necrosis factor receptor-associated factor 2
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Induction of NF-[kappa]B-dependent transcription requires phosphorylation and 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 factor receptor-associated factor 2 (TRAF2) plays a role in NF-[kappa]B activation in response to cytokines such as tumor necrosis factor [alpha] (TNF[alpha]). 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-[kappa]B[alpha] 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. Never theless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k-/- embryonic fibroblasts and thymocytes do not display increased sensitivity to TNF[alpha]-induced apoptosis. In response to either TNF[alpha] or IL-1 induction, t2k-/- embryonic fibroblasts exhibit normal degradation of I-[kappa]B and [kappa]B-binding activity. However, NF-[kappa]B-directed transcription is dramatically reduced. These results demonstrate that, like I-[kappa]B kinase [beta] and the RelA subunit of NF-[kappa]B, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF-[kappa]B-directed transcription, apparently independent of I-[kappa]B degradation and NF-[kappa]B DNA binding.
ISSN:0261-4189
1460-2075