title: LUBAC regulates NF-κB activation upon genotoxic stress by promoting linear ubiquitination of NEMO.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Cancer Research, Memphis, TN, USA.
authors.forename: Jixiao
authors.initials: J
authors.lastname: Niu
authors.forename: Yuling
authors.initials: Y
authors.lastname: Shi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Wu
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C491731:IKBKG protein, human; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase