Distinct roles of IκB proteins in regulating constitutive NF-κB activity

Abstract

The inhibitor of NF-κB (IκB) family of proteins is believed to regulate NF-κB activity by cytoplasmic sequestration. We show that in cells depleted of IκBα, IκBβ and IκBε proteins, a small fraction of p65 binds DNA and leads to constitutive activation of NF-κB target genes, even without stimulation, whereas most of the p65 remains cytoplasmic. These results indicate that although IκBα, IκBβ and IκBε proteins could be dispensable for cytoplasmic retention of NF-κB, they are essential for preventing NF-κB-dependent gene expression in the basal state. We also show that in the absence of IκBα, IκBβ and IκBε proteins, cytoplasmic retention of NF-κB by other cellular proteins renders the pathway unresponsive to activation.

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Figure 1: Regulation of NF-κB in cells devoid of three IκB members.
Figure 2: Constitutive activation but severe reduction of stimulus responsiveness of NF-κB in cells depleted of IκBα, IκBβ and IκBε proteins.

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Acknowledgements

We wish to thank A. Hoffmann and D. Baltimore for sharing unpublished information and for insights into this work. We thank C. Rothlin, O. Singer, G. Ghosh, N. Tonnu and B. Coyne for suggestions and help. V.T. is supported by a career development fellowship from the Leukemia and Lymphoma Society. I.M.V. is an American Cancer Society Professor of Molecular Biology and is supported by grants from the NIH, the Wayne and Gladys Valley Foundation, the Larry L. Hillblom Foundation, Inc., the Lebensfeld Foundation, the Merck Research Laboratories and the H.N. and Frances C. Berger Foundation.

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Correspondence to Inder M Verma.

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The authors declare no competing financial interests.

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Supplementary figures S1, S2, S3 and Supplementary methods (PDF 337 kb)

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