Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress.
The transcription factor NF-kappaB is critical for setting the cellular sensitivities to apoptotic stimuli, including DNA damaging anticancer agents. Central to NF-kappaB signaling pathways is NEMO/IKKgamma, the regulatory subunit of the cytoplasmic IkappaB kinase (IKK) complex. While NF-kappaB activation by genotoxic stress provides an attractive paradigm for nuclear-to-cytoplasmic signaling pathways, the mechanism by which nuclear DNA damage modulates NEMO to activate cytoplasmic IKK remains unknown. Here, we show that genotoxic stress causes nuclear localization of IKK-unbound NEMO via site-specific SUMO-1 attachment. Surprisingly, this sumoylation step is ATM-independent, but nuclear localization allows subsequent ATM-dependent ubiquitylation of NEMO to ultimately activate IKK in the cytoplasm. Thus, genotoxic stress induces two independent signaling pathways, SUMO-1 modification and ATM activation, which work in concert to sequentially cause nuclear targeting and ubiquitylation of free NEMO to permit the NF-kappaB survival pathway. These SUMO and ubiquitin modification pathways may serve as anticancer drug targets.
Huang
Tony T
TT
Department of Pharmacology, University of Wisconsin-Madison, 301 SMI, 1300 University Avenue, Madison, WI 53706, USA.
Wuerzberger-Davis
Shelly M
SM
Wu
Zhao-Hui
ZH
Miyamoto
Shigeki
S
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D019556:COS Cells; D018797:Cell Cycle Proteins; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins; D006801:Humans; D051550:I-kappa B Kinase; D008239:Lysine / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D025842:SUMO-1 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D008239:Lysine