ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-Mediated IKK activation in response to genotoxic stress

Zhao Hui Wu, Ee Tsin Wong, Yuling Shi, Jixiao Niu, Zhijian Chen, Shigeki Miyamoto, Vinay Tergaonkar

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

Activation of the transcription factor NF-κB by multiple genotoxic stimuli modulates cancer cell survival. This response is mediated by a conserved pathway involving the nuclear ATM kinase and cytoplasmic IκB kinase (IKK); however, the molecular link between them remains incompletely understood. Here we show that ATM activates the IKK kinase TAK1 in a manner dependent on IKKγ/NEMO and ELKS (a protein rich in glutamate, leucine, lysine, and serine). K63-linked polyubiquitination of ELKS, dependent on the ubiquitin ligase XIAP and the conjugating enzyme UBC13, allows ELKS association with TAK1 via its ubiquitin-binding subunits TAB2/3. Although NEMO mutants defective in ubiquitin binding permit ATM-dependent TAK1 activation, they block NEMO association with ELKS and IKK activation. Thus, ATM- and NEMO-dependent ubiquitination of ELKS leads to the ubiquitin-dependent assembly of TAK1/TAB2/3 and NEMO/IKK complexes, resulting in IKK and NF-κB activation following genotoxic stimuli.

Original languageEnglish (US)
Pages (from-to)75-86
Number of pages12
JournalMolecular Cell
Volume40
Issue number1
DOIs
Publication statusPublished - Oct 8 2010

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)

Cite this