IκBβ, but Not IκBα, Functions as a Classical Cytoplasmic Inhibitor of NF-κB Dimers by Masking Both NF-κB Nuclear Localization Sequences in Resting Cells*

By S. Malek, Yi Chen, T. Huxford, G. Ghosh. Journal of Biological Chemistry, 2001

158 citations recorded by the source corpus.

NF-κB dimers, inhibitor IκB proteins, and NF-κB·IκB complexes exhibit distinct patterns in partitioning between nuclear and cytoplasmic cellular compartments. IκB-dependent modulation of NF-κB subcellular localization represents one of the more poorly understood processes in the NF-κB signaling pathway. In this study, we have combined in vitro biochemical and cell-based methods to elucidate differences in NF-κB regulation exhibited by the inhibitors IκBβ and IκBα. We show that although both IκBα and IκBβ bind to NF-κB with similar global architecture and stability, significant differences exist that contribute to their unique functional roles. IκBβ derives its high affinity toward NF-κB dimers by binding to both NF-κB subunit nuclear localization signals. In contrast, IκBα contacts only one NF-κB NLS and employs its carboxyl-terminal proline, glutamic acid, serine, and threonine-rich region for high affinity NF-κB binding. We show that the presence of one free NLS in the NF-κB·IκBα complex renders it a dynamic nucleocytoplasmic complex, whereas NF-κB·IκBβ complexes are localized to the cytoplasm of resting cells.

Subfields: Cancer Research, Molecular Biology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/00246eaac8dd8bc298a1663dc9613df0c5ebc6bc

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In Cancer Research

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Citations in the corpus

• Molecular Basis of NF-κB Signaling (2013, background): “The interaction between the NEMOZF and ubiquitin resembles previously solved interactions between α-helical ubiquitin-binding domains and ubiquitin; the amphipathic α-helix of the NEMO ZF binds to a hydrophobic patch centered around residue Ile44 of ubiquitin (12, 27, 38, 39, 46, 73, 102, 107, 108).”
• Signaling via the NFκB system (2016, background): “There is also evidence that IκBα and ε preferentially inhibit distinct NFκB family members.(64) In B cells, IκBε has been shown to play a key role in regulating cRel containing NFκB dimers, with loss of IκBε resulting in increased B-cell survival and proliferation.”