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

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

Research output: Contribution to journalArticle

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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
StatePublished - Oct 8 2010

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Ubiquitination
Ubiquitin
DNA Damage
Phosphotransferases
Ligases
Leucine
Serine
Lysine
Glutamic Acid
Cell Survival
Transcription Factors
Enzymes
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-Mediated IKK activation in response to genotoxic stress. / Wu, Zhaohui; Wong, Ee Tsin; Shi, Yuling; Niu, Jixiao; Chen, Zhijian; Miyamoto, Shigeki; Tergaonkar, Vinay.

In: Molecular Cell, Vol. 40, No. 1, 08.10.2010, p. 75-86.

Research output: Contribution to journalArticle

Wu, Zhaohui ; Wong, Ee Tsin ; Shi, Yuling ; Niu, Jixiao ; Chen, Zhijian ; Miyamoto, Shigeki ; Tergaonkar, Vinay. / ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-Mediated IKK activation in response to genotoxic stress. In: Molecular Cell. 2010 ; Vol. 40, No. 1. pp. 75-86.
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AU - Niu, Jixiao

AU - Chen, Zhijian

AU - Miyamoto, Shigeki

AU - Tergaonkar, Vinay

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