LUBAC regulates NF-?B activation upon genotoxic stress by promoting linear ubiquitination of NEMO.

ABSTRACT: The transcription factor nuclear factor ?B (NF-?B) regulates various cellular processes such as inflammation and apoptosis. The NF-?B essential modulator (NEMO/IKK?) is indispensable for NF-?B activation by diverse stimuli including genotoxic stress. Here, we show that NEMO linear ubiquitination on K285/309 is critical for genotoxic NF-?B activation. The E3 ligase linear ubiquitin chain assembly complex (LUBAC) facilitates NEMO linear ubiquitination upon genotoxic stress. Inhibiting LUBAC function interrupts the genotoxic NF-?B 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-?B activation and protects cells from DNA damage-induced apoptosis.

SUBMITTER: Niu J 

PROVIDER: S-EPMC3173792 | biostudies-other | 2011 Aug

REPOSITORIES: biostudies-other