Authors: Zhao-Hui Wu1,2,*, Ee Tsin Wong3*, Yuling Shi1,2, Jixiao Niu1,2, Zhijian Chen4, Shigeki Miyamoto5 and Vinay Tergaonkar3.
1 - Department of Pathology and Laboratory Medicine
2 - Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163
3 - Institute of molecular and Cell Biology. Biopolis A*STAR, Singapore 138673, Singapore
4 - Howard Hughes Medical Institute, Department of molecular biology, University of Texas Southwestern Medical Center, Dallas, TX75390
5 - Department of Pharmacology, University of Wisconsin-Madison, Madison, WI 53705
* These authors contributed equally.
Published in Molecular Cell, Oct 8, 2010 Epub ahead of print
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.