Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor α- and interleukin-1 β-induced IKK/NF-κB and JNK/AP-1 activation

Academic Article


  • Transforming growth factor-β-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor α (TNFα)-and interleukin-1β (IL-1β)-induced IκB kinase (IKK)/nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) activation. Here we report that TNFα and IL-1β induce Lys63-linked TAK1 polyubiquitination at the Lys158 residue within the kinase domain. Tumor necrosis factor receptor-associated factors 2 and 6 (TRAF2 and -6) act as the ubiquitin E3 ligases to mediate Lys63-linkedTAK1polyubiquitination at the Lys158 residue in vivo and in vitro. Lys63-linked TAK1 polyubiquitination at the Lys158 residue is required for TAK1-mediated IKK complex recruitment. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild type or a TAK1 mutant containing a K158R mutation revealed the importance of this site in TNFα and IL-1β-mediated IKK/NF-κB and JNK/AP-1 activation as well as IL-6 gene expression. Our findings demonstrate that Lys63-linked polyubiquitination of TAK1 at Lys158 is essential for its own kinase activation and its ability to mediate its downstream signal transduction pathways in response to TNFα and IL-1β stimulation. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
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    Author List

  • Fan Y; Yu Y; Shi Y; Sun W; Xie M; Ge N; Mao R; Chang A; Xu G; Schneider MD
  • Start Page

  • 5347
  • End Page

  • 5360
  • Volume

  • 285
  • Issue

  • 8