Inhibitor of kappaB kinase beta regulates redox homeostasis by controlling the constitutive levels of glutathione.
Cytokine-activated inhibitor of kappaB kinase beta (IKKbeta) is a key mediator of immune and inflammatory responses, but recent studies suggest that IKKbeta is also required for tissue homeostasis in physiopathological processes. Here we report a novel role for IKKbeta in maintenance of constitutive levels of the redox scavenger GSH. Inactivation of IKKbeta by genetic or pharmacological means results in low cellular GSH content and marked reduction of redox potential. Similar to Ikkbeta(-/-) cells, Tnfr1(-/-) and p65(-/-) cells are also GSH-deficient. As a consequence, cells deficient in IKKbeta signaling are extremely susceptible to toxicity caused by environmental and pharmacological agents, including oxidants, genotoxic agents, microtubule toxins, and arsenic. GSH biosynthesis depends on the activity of the rate-limiting enzyme glutamate-cysteine ligase (GCL), consisting of a catalytic subunit (GCLC) and a modifier subunit (GCLM). We found that loss of IKKbeta signaling significantly reduces basal NF-kappaB activity and decreases binding of NF-kappaB to the promoters of Gclc and Gclm, leading to reduction of GCLC and GCLM expression. Conversely, overexpression of GCLC and GCLM in IKKbeta-null cells partially restores GSH content and prevents stress-induced cytotoxicity. We suggest that maintenance of GSH is a novel physiological role of the IKKbeta-NF-kappaB signaling cascade to prevent oxidative damage and preserve the functional integrity of the cells.
Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Zhimin
Z
Peng
Esmond
E
Geh
Liang
L
Chen
Qinghang
Q
Meng
Yunxia
Y
Fan
Maureen
M
Sartor
Howard G
HG
Shertzer
Zheng-Gang
ZG
Liu
Alvaro
A
Puga
Ying
Y
Xia
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D017931:DNA Primers; D017930:Genes, Reporter; D005978:Glutathione / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics*; D010084:Oxidation-Reduction; D010957:Plasmids; D017382:Reactive Oxygen Species / Q000378:metabolism
D017931:DNA Primers; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D008156:Luciferases; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D005978:Glutathione