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

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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. © 2010 Elsevier Inc.

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Wu, Z. H., Wong, E. T., Shi, Y., Niu, J., Chen, Z., Miyamoto, S., & Tergaonkar, V. (2010). ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-Mediated IKK activation in response to genotoxic stress. Molecular Cell, 40(1), 75–86. https://doi.org/10.1016/j.molcel.2010.09.010

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