RT Journal Article
SR Electronic
T1 Inhibitor of κB Kinase β Regulates Redox Homeostasis by Controlling the Constitutive Levels of Glutathione
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 784
OP 792
DO 10.1124/mol.109.061424
VO 77
IS 5
A1 Zhimin Peng
A1 Esmond Geh
A1 Liang Chen
A1 Qinghang Meng
A1 Yunxia Fan
A1 Maureen Sartor
A1 Howard G. Shertzer
A1 Zheng-Gang Liu
A1 Alvaro Puga
A1 Ying Xia
YR 2010
UL http://molpharm.aspetjournals.org/content/77/5/784.abstract
AB Cytokine-activated inhibitor of κB kinase β (IKKβ) is a key mediator of immune and inflammatory responses, but recent studies suggest that IKKβ is also required for tissue homeostasis in physiopathological processes. Here we report a novel role for IKKβ in maintenance of constitutive levels of the redox scavenger GSH. Inactivation of IKKβ by genetic or pharmacological means results in low cellular GSH content and marked reduction of redox potential. Similar to Ikkβ(−/−) cells, Tnfr1(−/−) and p65(−/−) cells are also GSH-deficient. As a consequence, cells deficient in IKKβ 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 IKKβ signaling significantly reduces basal NF-κB activity and decreases binding of NF-κB to the promoters of Gclc and Gclm, leading to reduction of GCLC and GCLM expression. Conversely, overexpression of GCLC and GCLM in IKKβ-null cells partially restores GSH content and prevents stress-induced cytotoxicity. We suggest that maintenance of GSH is a novel physiological role of the IKKβ-NF-κB signaling cascade to prevent oxidative damage and preserve the functional integrity of the cells.U.S. Government work not protected by U.S. copyright