LUBAC regulates NF-κB activation upon genotoxic stress by promoting linear ubiquitination of NEMO

EMBO J. 2011 Aug 2;30(18):3741-53. doi: 10.1038/emboj.2011.264.


The transcription factor nuclear factor κB (NF-κB) regulates various cellular processes such as inflammation and apoptosis. The NF-κB essential modulator (NEMO/IKKγ) is indispensable for NF-κB activation by diverse stimuli including genotoxic stress. Here, we show that NEMO linear ubiquitination on K285/309 is critical for genotoxic NF-κB activation. The E3 ligase linear ubiquitin chain assembly complex (LUBAC) facilitates NEMO linear ubiquitination upon genotoxic stress. Inhibiting LUBAC function interrupts the genotoxic NF-κB signalling cascade by attenuating the activation of IKK and TAK1 in response to DNA damage. We further show that the linear ubiquitination of NEMO is a cytoplasmic event, potentially downstream of NEMO nuclear exportation. Moreover, ELKS ubiquitination appears to facilitate linear ubiquitination of NEMO through stabilizing NEMO:LUBAC association upon DNA damage. Deubiquitinating enzyme CYLD inhibits NEMO linear ubiquitination, possibly by disassembling both K63-linked and linear polyubiquitin. We also found that abrogating linear ubiquitination of NEMO significantly increased genotoxin-induced apoptosis, resulting in enhanced sensitivity to chemodrug in cancer cells. Therefore, LUBAC-dependent NEMO linear ubiquitination is critical for genotoxic NF-κB activation and protects cells from DNA damage-induced apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA Damage*
  • Humans
  • I-kappa B Kinase / metabolism*
  • NF-kappa B / biosynthesis*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • IKBKG protein, human
  • NF-kappa B
  • Ubiquitin-Protein Ligases
  • I-kappa B Kinase