ATM- and NEMO-Dependent ELKS Ubiquitination Coordinates TAK1-Mediated IKK Activation in Response to Genotoxic Stress

SummaryActivation 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (249 K)Download as PowerPoint slideHighlights► DNA damage activated TAK1 and IKK via ATM, NEMO, and ELKS ► ATM and NEMO promoted ELKS K63-ubiquitination via XIAP ► Ubiquitinated ELKS assembled TAK1-TAB2/3 and IKK-NEMO complex to activate IKK ► NEMO acted both upstream and downstream of TAK1 in DNA damage-NF-κB signaling