| First Author | Niu J | Year | 2011 |
| Journal | EMBO J | Volume | 30 |
| Issue | 18 | Pages | 3741-53 |
| PubMed ID | 21811235 | Mgi Jnum | J:200492 |
| Mgi Id | MGI:5508721 | Doi | 10.1038/emboj.2011.264 |
| Citation | Niu J, et al. (2011) LUBAC regulates NF-kappaB activation upon genotoxic stress by promoting linear ubiquitination of NEMO. EMBO J 30(18):3741-53 |
| abstractText | The transcription factor nuclear factor kappaB (NF-kappaB) regulates various cellular processes such as inflammation and apoptosis. The NF-kappaB essential modulator (NEMO/IKKgamma) is indispensable for NF-kappaB activation by diverse stimuli including genotoxic stress. Here, we show that NEMO linear ubiquitination on K285/309 is critical for genotoxic NF-kappaB activation. The E3 ligase linear ubiquitin chain assembly complex (LUBAC) facilitates NEMO linear ubiquitination upon genotoxic stress. Inhibiting LUBAC function interrupts the genotoxic NF-kappaB 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-kappaB activation and protects cells from DNA damage-induced apoptosis. |
