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Brap2 regulates temporal control of NF-?B localization mediated by inflammatory response.

ABSTRACT: Nuclear factor-kappaB (NF-?B) is critical for the expression of multiple genes involved in inflammatory responses and cellular survival. NF-?B is normally sequestered in the cytoplasm through interaction with an inhibitor of NF-?B (I?B), but inflammatory stimulation induces proteasomal degradation of I?B, followed by NF-?B nuclear translocation. The degradation of I?B is mediated by a SCF (Skp1-Cullin1-F-box protein)-type ubiquitin ligase complex that is post-translationaly modified by a ubiquitin-like molecule Nedd8. In this study, we report that BRCA1-associated protein 2 (Brap2) is a novel Nedd8-binding protein that interacts with SCF complex, and is involved in NF-?B translocation following TNF-? stimulation. We also found a putative neddylation site in Brap2 associated with NF-?B activity. Our findings suggest that Brap2 is a novel modulator that associates with SCF complex and controls TNF-?-induced NF-?B nuclear translocation.

SUBMITTER: Takashima O

PROVIDER: S-EPMC3598860 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Brap2 regulates temporal control of NF-κB localization mediated by inflammatory response.

Takashima Osamu O Tsuruta Fuminori F Kigoshi Yu Y Nakamura Shingo S Kim Jaehyun J Katoh Megumi C MC Fukuda Tomomi T Irie Kenji K Chiba Tomoki T

PloS one 20130315 3

Nuclear factor-kappaB (NF-κB) is critical for the expression of multiple genes involved in inflammatory responses and cellular survival. NF-κB is normally sequestered in the cytoplasm through interaction with an inhibitor of NF-κB (IκB), but inflammatory stimulation induces proteasomal degradation of IκB, followed by NF-κB nuclear translocation. The degradation of IκB is mediated by a SCF (Skp1-Cullin1-F-box protein)-type ubiquitin ligase complex that is post-translationaly modified by a ubiquit ...[more]

PMID: 23554956

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Project description:BackgroundAbility to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Heat Shock (HS) affects the signalling and gene expression responses of the Nuclear Factor κB (NF-κB) transcription factor, a critical regulator of proliferation and inflammation, however, our quantitative understanding of how cells sense and adapt to temperature changes is limited.MethodsWe used live-cell time-lapse microscopy and mathematical modelling to understand the signalling of the NF-κB system in the human MCF7 breast adenocarcinoma cells in response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines, following exposure to a 37-43 °C range of physiological and clinical temperatures.ResultsWe show that exposure to 43 °C 1 h HS inhibits the immediate NF-κB signalling response to TNFα and IL1β stimulation although uptake of cytokines is not impaired. Within 4 h after HS treatment IL1β-induced NF-κB responses return to normal levels, but the recovery of the TNFα-induced responses is still affected. Using siRNA knock-down of Heat Shock Factor 1 (HSF1) we show that this stimulus-specificity is conferred via the Inhibitory κB kinase (IKK) signalosome where HSF1-dependent feedback regulates TNFα, but not IL1β-mediated IKK recovery post HS. Furthermore, we demonstrate that through the temperature-dependent denaturation and recovery of IKK, TNFα and IL1β-mediated signalling exhibit different temperature sensitivity and adaptation to repeated HS when exposed to a 37-43 °C temperature range. Specifically, IL1β-mediated NF-κB responses are more robust to temperature changes in comparison to those induced by TNFα treatment.ConclusionsWe demonstrate that the kinetics of the NF-κB system following temperature stress is cytokine specific and exhibit differential adaptation to temperature changes. We propose that this differential temperature sensitivity is mediated via the IKK signalosome, which acts as a bona fide temperature sensor trough the HSR cross-talk. This novel quantitative understanding of NF-κB and HSR interactions is fundamentally important for the potential optimization of therapeutic hyperthermia protocols. Video Abstract.

Dataset Information

Brap2 regulates temporal control of NF-?B localization mediated by inflammatory response.

Publications

Brap2 regulates temporal control of NF-κB localization mediated by inflammatory response.

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