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Stimulation-Dependent IκBα Phosphorylation Marks the NF- κB Inhibitor for Degradation Via the Ubiquitin-Proteasome Pathway

Irit Alkalay, Avraham Yaron, Ada Hatzubai, Amir Orian, Aaron Ciechanover and Yinon Ben-Neriah
Proceedings of the National Academy of Sciences of the United States of America
Vol. 92, No. 23 (Nov. 7, 1995), pp. 10599-10603
Stable URL: http://www.jstor.org/stable/2368835
Page Count: 5
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Stimulation-Dependent IκBα Phosphorylation Marks the NF- κB Inhibitor for Degradation Via the Ubiquitin-Proteasome Pathway
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Abstract

The nuclear translocation of NF-κ B follows the degradation of its inhibitor, Iκ Bα, an event coupled with stimulation-dependent inhibitor phosphorylation. Prevention of the stimulation-dependent phosphorylation of Iκ Bα, either by treating cells with various reagents or by mutagenesis of certain putative Iκ Bα phosphorylation sites, abolishes the inducible degradation of Iκ Bα. Yet, the mechanism coupling the stimulation-induced phosphorylation with the degradation has not been resolved. Recent reports suggest a role for the proteasome in Iκ Bα degradation, but the mode of substrate recognition and the involvement of ubiquitin conjugation as a targeting signal have not been addressed. We show that of the two forms of Iκ Bα recovered from stimulated cells in a complex with RelA and p50, only the newly phosphorylated form, pIκ Bα, is a substrate for an in vitro reconstituted ubiquitin-proteasome system. Proteolysis requires ATP, ubiquitin, a specific ubiquitin-conjugating enzyme, and other ubiquitin-proteasome components. In vivo, inducible Iκ Bα degradation requires a functional ubiquitin-activating enzyme and is associated with the appearance of high molecular weight adducts of Iκ Bα. Ubiquitin-mediated protein degradation may, therefore, constitute an integral step of a signal transduction process.

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