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p100/IκBδ sequesters and inhibits NF-κB through kappaBsome formation.

Tao Z, Fusco A, Huang DB, Gupta K, Young Kim D, Ware CF, Van Duyne GD, Ghosh G
Proc Natl Acad Sci U S A 111 15946-51 (2014)
Cited: 35 times
EuropePMC logo PMID: 25349408

Abstract

Degradation of I kappaB (κB) inhibitors is critical to activation of dimeric transcription factors of the NF-κB family. There are two types of IκB inhibitors: the prototypical IκBs (IκBα, IκBβ, and IκBε), which form low-molecular-weight (MW) IκB:NF-κB complexes that are highly stable, and the precursor IκBs (p105/IκBγ and p100/IκBδ), which form high-MW assemblies, thereby suppressing the activity of nearly half the cellular NF-κB [Savinova OV, Hoffmann A, Ghosh G (2009) Mol Cell 34(5):591-602]. The identity of these larger assemblies and their distinct roles in NF-κB inhibition are unknown. Using the X-ray crystal structure of the C-terminal domain of p100/IκBδ and functional analysis of structure-guided mutants, we show that p100/IκBδ forms high-MW (IκBδ)4:(NF-κB)4 complexes, referred to as kappaBsomes. These IκBδ-centric "kappaBsomes" are distinct from the 2:2 complexes formed by IκBγ. The stability of the IκBδ tetramer is enhanced upon association with NF-κB, and hence the high-MW assembly is essential for NF-κB inhibition. Furthermore, weakening of the IκBδ tetramer impairs both its association with NF-κB subunits and stimulus-dependent processing into p52. The unique ability of p100/IκBδ to stably interact with all NF-κB subunits by forming kappaBsomes demonstrates its importance in sequestering NF-κB subunits and releasing them as dictated by specific stimuli for developmental programs.

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  1. p100/IκBδ sequesters and inhibits NF-κB through kappaBsome formation. Tao Z, Fusco A, Huang DB, Gupta K, Young Kim D, Ware CF, Van Duyne GD, Ghosh G. Proc Natl Acad Sci U S A 111 15946-15951 (2014)
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  2. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Zinatizadeh MR, Schock B, Chalbatani GM, Zarandi PK, Jalali SA, Miri SR. Genes Dis 8 287-297 (2021)
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  18. A Kinase Assay for Measuring the Activity of the NIK-IKK1 Complex Induced via the Noncanonical NF-κB Pathway. Mukherjee T, Ratra Y, Banoth B, Deka A, Polley S, Basak S. Methods Mol Biol 2366 165-181 (2021)
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