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Novel insights into the cellular mechanisms of the anti-inflammatory effects of NF-kappaB essential modulator binding domain peptides
Novel insights into the cellular mechanisms of the anti-inflammatory effects of NF-kappaB essential modulator binding domain peptides
- Source :
- The Journal of Biological Chemistry
- Publication Year :
- 2010
-
Abstract
- The classical nuclear factor kappaB (NF-kappaB) signaling pathway is under the control of the IkappaB kinase (IKK) complex, which consists of IKK-1, IKK-2, and NF-kappaB essential modulator (NEMO). This complex is responsible for the regulation of cell proliferation, survival, and differentiation. Dysregulation of this pathway is associated with several human diseases, and as such, its inhibition offers an exciting opportunity for therapeutic intervention. NEMO binding domain (NBD) peptides inhibit the binding of recombinant NEMO to IKK-2 in vitro. However, direct evidence of disruption of this binding by NBD peptides in biological systems has not been provided. Using a cell system, we expanded on previous observations to show that NBD peptides inhibit inflammation-induced but not basal cytokine production. We report that these peptides cause the release of IKK-2 from an IKK complex and disrupt NEMO-IKK-2 interactions in cells. We demonstrate that by interfering with NEMO-IKK-2 interactions, NBD peptides inhibit IKK-2 phosphorylation, without affecting signaling intermediates upstream of the IKK complex of the NF-kappaB pathway. Furthermore, in a cell-free system of IKK complex activation by TRAF6 (TNF receptor-associated factor 6), we show that these peptides inhibit the ability of this complex to phosphorylate downstream substrates, such as p65 and inhibitor of kappaB alpha (IkappaB alpha). Thus, consistent with the notion that NEMO regulates IKK-2 catalytic activity by serving as a scaffold, appropriately positioning IKK-2 for activation by upstream kinase(s), our findings provide novel insights into the molecular mechanisms by which NBD peptides exert their anti-inflammatory effects in cells.
- Subjects :
- Peptide Interactions
Cell Survival
Cellular differentiation
cells
Anti-Inflammatory Agents
IκB kinase
Biology
Biochemistry
environment and public health
NF-κB
Protein Phosphorylation
chemistry.chemical_compound
Humans
Phosphorylation
CHUK
skin and connective tissue diseases
Molecular Biology
Cytokine
Cells, Cultured
Cell Proliferation
TNF Receptor-Associated Factor 6
Inflammation
I-Kappa-B Kinase
Transcription Factor RelA
Cell Differentiation
Cell Biology
Cell biology
I-kappa B Kinase
Protein Structure, Tertiary
IκBα
enzymes and coenzymes (carbohydrates)
chemistry
Multiprotein Complexes
Cytokines
Fibroblast
Signal transduction
biological phenomena, cell phenomena, and immunity
Peptides
Protein Kinases
Binding domain
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 285
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....0554c30fdfc058636a2f89f8139d732c