Rapid proteolysis of IκB-α is necessary for activation of transcription factor NF-κB

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Abstract

INDUCIBLE gene expression in eukaryotes is mainly controlled by the activity of transcriptional activator proteins, such as NF-κB (refs 1–3), a factor activated upon treatment of cells with phorbolesters, lipopolysaccharide4, interleukin-1 and tumour necrosis factor-α5. Activation of NF-κB involves release of the inhibitory sub-unit IκB from a cytoplasmic complex with the DNA-binding subunits Rel-A (formerly p65) and p50 (refs 6, 7). Cell-free experiments have suggested that protein kinase C and other kinases transfer phosphoryl groups onto IκB causing release of IκB and subsequent activation of NF-κB8–10. Here we report that IκB-α (formerly MAD-3)11 is degraded in cells after stimulation with phorbol ester, interleukin-1, lipopolysaccharide and tumour necrosis factor-α, an event coincident with the appearance of active NF-κB. Treatment of cells with various protease inhibitors or an antioxidant completely prevented the inducible decay of IκB-α as well as the activation of NFκcB. Our findings suggest that the activation of NF-κB relies on an inducible degradation of IκB-α through a cytoplasmic, chymotrypsin-like protease. In intact cells, phosphorylation of IκB-α is apparently not sufficient for activation of NF-κB.

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