Abstract
The transcription factor NF-κB plays a pivotal role in innate immunity in response to a variety of stimuli, and the coordinated regulation of this pathway determines the proper host responses to extracellular signals. In this study, we identified RACK1 as a novel negative regulator of NF-κB signaling, NF-κB-mediated cytokine induction and inflammatory reactions. RACK1 physically associates with the IKK complex in a TNF-triggered manner. This interaction interferes with the recruitment of the IKK complex to TRAF2, which is a critical step for IKK phosphorylation and subsequent activation triggered by TNF. By modulating the interaction between TRAF2 and IKK, RACK1 regulates the levels of NF-κB activation in response to different intensities of stimuli. Our findings suggest that RACK1 plays an important role in controlling the sensitivity of TNF-triggered NF-κB signaling by regulating IKK activation and provide new insight into the negative regulation of inflammatory reactions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cytokines / metabolism
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Enzyme Activation / drug effects
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GTP-Binding Proteins / antagonists & inhibitors
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / metabolism*
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HEK293 Cells
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HeLa Cells
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Humans
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I-kappa B Kinase / chemistry
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I-kappa B Kinase / metabolism*
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NF-kappa B / metabolism*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / metabolism*
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Phosphorylation / drug effects
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Protein Binding
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Protein Structure, Tertiary
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RNA Interference
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RNA, Small Untranslated / metabolism
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Receptors for Activated C Kinase
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Receptors, Cell Surface / antagonists & inhibitors
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Receptors, Cell Surface / chemistry
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Receptors, Cell Surface / metabolism*
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Signal Transduction / drug effects
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TNF Receptor-Associated Factor 2 / chemistry
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TNF Receptor-Associated Factor 2 / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Cytokines
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NF-kappa B
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Neoplasm Proteins
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RACK1 protein, human
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RNA, Small Untranslated
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Receptors for Activated C Kinase
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Receptors, Cell Surface
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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I-kappa B Kinase
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GTP-Binding Proteins