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P100/I?B? sequesters and inhibits NF-?B through kappaBsome formation.

ABSTRACT: Degradation of I kappaB (?B) inhibitors is critical to activation of dimeric transcription factors of the NF-?B family. There are two types of I?B inhibitors: the prototypical I?Bs (I?B?, I?B?, and I?B?), which form low-molecular-weight (MW) I?B:NF-?B complexes that are highly stable, and the precursor I?Bs (p105/I?B? and p100/I?B?), which form high-MW assemblies, thereby suppressing the activity of nearly half the cellular NF-?B [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-?B inhibition are unknown. Using the X-ray crystal structure of the C-terminal domain of p100/I?B? and functional analysis of structure-guided mutants, we show that p100/I?B? forms high-MW (I?B?)4:(NF-?B)4 complexes, referred to as kappaBsomes. These I?B?-centric "kappaBsomes" are distinct from the 2:2 complexes formed by I?B?. The stability of the I?B? tetramer is enhanced upon association with NF-?B, and hence the high-MW assembly is essential for NF-?B inhibition. Furthermore, weakening of the I?B? tetramer impairs both its association with NF-?B subunits and stimulus-dependent processing into p52. The unique ability of p100/I?B? to stably interact with all NF-?B subunits by forming kappaBsomes demonstrates its importance in sequestering NF-?B subunits and releasing them as dictated by specific stimuli for developmental programs.

SUBMITTER: Tao Z

PROVIDER: S-EPMC4234596 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Tao Zhihua Z Fusco Amanda A Huang De-Bin DB Gupta Kushol K Young Kim Daniel D Ware Carl F CF Van Duyne Gregory D GD Ghosh Gourisankar G

Proceedings of the National Academy of Sciences of the United States of America 20141027 45

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]. ...[more]

PMID: 25349408

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Project description:Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.

Dataset Information

P100/I?B? sequesters and inhibits NF-?B through kappaBsome formation.

Publications

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

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