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

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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.