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Science 289 (5484): 1550-1554

Copyright © 2000 by the American Association for the Advancement of Science

Selective Inhibition of NF-kappa B Activation by a Peptide That Blocks the Interaction of NEMO with the Ikappa B Kinase Complex

Michael J. May,1 Fulvio D'Acquisto,1 Lisa A. Madge,2 Judith Glöckner,1 Jordan S. Pober,2 Sankar Ghosh1*

Activation of the transcription factor nuclear factor (NF)-kappa B by proinflammatory stimuli leads to increased expression of genes involved in inflammation. Activation of NF-kappa B requires the activity of an inhibitor of kappa B (Ikappa B)-kinase (IKK) complex containing two kinases (IKKalpha and IKKbeta ) and the regulatory protein NEMO (NF-kappa B essential modifier). An amino-terminal alpha -helical region of NEMO associated with a carboxyl-terminal segment of IKKalpha and IKKbeta that we term the NEMO-binding domain (NBD). A cell-permeable NBD peptide blocked association of NEMO with the IKK complex and inhibited cytokine-induced NF-kappa B activation and NF-kappa B-dependent gene expression. The peptide also ameliorated inflammatory responses in two experimental mouse models of acute inflammation. The NBD provides a target for the development of drugs that would block proinflammatory activation of the IKK complex without inhibiting basal NF-kappa B activity.

1 Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
2 Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
*   To whom correspondence should be addressed. E-mail: sankar.ghosh{at}yale.edu

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H. Slevogt, B. Schmeck, C. Jonatat, J. Zahlten, W. Beermann, V. van Laak, B. Opitz, S. Dietel, P. D. N'Guessan, S. Hippenstiel, et al. (2006)
Am J Physiol Lung Cell Mol Physiol 290, L818-L826
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A Point Mutation in NEMO Associated with Anhidrotic Ectodermal Dysplasia with Immunodeficiency Pathology Results in Destabilization of the Oligomer and Reduces Lipopolysaccharide- and Tumor Necrosis Factor-mediated NF-{kappa}B Activation.
E. Vinolo, H. Sebban, A. Chaffotte, A. Israel, G. Courtois, M. Veron, and F. Agou (2006)
J. Biol. Chem. 281, 6334-6348
   Abstract »    Full Text »    PDF »
Disruption of SLP-76 Interaction with Gads Inhibits Dynamic Clustering of SLP-76 and Fc{varepsilon}RI Signaling in Mast Cells.
M. A. Silverman, J. Shoag, J. Wu, and G. A. Koretzky (2006)
Mol. Cell. Biol. 26, 1826-1838
   Abstract »    Full Text »    PDF »
The Kinase Complex Responsible for IRF-3-Mediated IFN-{beta} Production in Myeloid Dendritic Cells (mDC).
M. Sasai, M. Matsumoto, and T. Seya (2006)
J. Biochem. 139, 171-175
   Abstract »    Full Text »    PDF »
Conjugated Linoleic Acid Promotes Human Adipocyte Insulin Resistance through NF{kappa}B-dependent Cytokine Production.
S. Chung, J. M. Brown, J. N. Provo, R. Hopkins, and M. K. McIntosh (2005)
J. Biol. Chem. 280, 38445-38456
   Abstract »    Full Text »    PDF »
Inhibition of Nuclear Translocation of Nuclear Factor-{kappa}B Despite Lack of Functional I{kappa}B{alpha} Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies.
R. K. Thomas, M. L. Sos, T. Zander, O. Mani, A. Popov, D. Berenbrinker, S. Smola-Hess, J. L. Schultze, and J. Wolf (2005)
Clin. Cancer Res. 11, 8186-8194
   Abstract »    Full Text »    PDF »
Positive Regulation of I{kappa}B Kinase Signaling by Protein Serine/Threonine Phosphatase 2A.
A. E. Kray, R. S. Carter, K. N. Pennington, R. J. Gomez, L. E. Sanders, J. M. Llanes, W. N. Khan, D. W. Ballard, and B. E. Wadzinski (2005)
J. Biol. Chem. 280, 35974-35982
   Abstract »    Full Text »    PDF »
Prevention of NF-{kappa}B activation in vivo by a cell-permeable NF-{kappa}B inhibitor peptide.
A. L. Mora, J. LaVoy, M. McKean, A. Stecenko, K. L. Brigham, R. Parker, and M. Rojas (2005)
Am J Physiol Lung Cell Mol Physiol 289, L536-L544
   Abstract »    Full Text »    PDF »
Bcl10 can promote survival of antigen-stimulated B lymphocytes.
M. T. Tian, G. Gonzalez, B. Scheer, and A. L. DeFranco (2005)
Blood 106, 2105-2112
   Abstract »    Full Text »    PDF »
Cationic cell-penetrating peptides interfere with TNF signalling by induction of TNF receptor internalization.
M. Fotin-Mleczek, S. Welte, O. Mader, F. Duchardt, R. Fischer, H. Hufnagel, P. Scheurich, and R. Brock (2005)
J. Cell Sci. 118, 3339-3351
   Abstract »    Full Text »    PDF »
NF-{kappa}B inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation.
B. Y. Kim, K. A. Kim, O. Kwon, S. O. Kim, M. S. Kim, B. S. Kim, W. K. Oh, G. D. Kim, M. Jung, and J. S. Ahn (2005)
Carcinogenesis 26, 1395-1403
   Abstract »    Full Text »    PDF »
Identification of Direct Genomic Targets Downstream of the Nuclear Factor-{kappa}B Transcription Factor Mediating Tumor Necrosis Factor Signaling.
B. Tian, D. E. Nowak, M. Jamaluddin, S. Wang, and A. R. Brasier (2005)
J. Biol. Chem. 280, 17435-17448
   Abstract »    Full Text »    PDF »
Nuclear Factor-{kappa}B-Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone.
A. H. Gordon, R. J. O'Keefe, E. M. Schwarz, R. N. Rosier, and J. E. Puzas (2005)
Cancer Res. 65, 3209-3217
   Abstract »    Full Text »    PDF »
PDK1 Nucleates T Cell Receptor-Induced Signaling Complex for NF-{kappa}B Activation.
K.-Y. Lee, F. D'Acquisto, M. S. Hayden, J.-H. Shim, and S. Ghosh (2005)
Science 308, 114-118
   Abstract »    Full Text »    PDF »
The nuclear factor {kappa}B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells.
R. B. Riggins, A. Zwart, R. Nehra, and R. Clarke (2005)
Mol. Cancer Ther. 4, 33-41
   Abstract »    Full Text »    PDF »
Inhibition of NF-{kappa}B Activation by Peptides Targeting NF-{kappa}B Essential Modulator (NEMO) Oligomerization.
F. Agou, G. Courtois, J. Chiaravalli, F. Baleux, Y.-M. Coic, F. Traincard, A. Israel, and M. Veron (2004)
J. Biol. Chem. 279, 54248-54257
   Abstract »    Full Text »    PDF »
Streptococcus pneumoniae-induced p38 MAPK-dependent Phosphorylation of RelA at the Interleukin-8 Promotor.
B. Schmeck, J. Zahlten, K. Moog, V. van Laak, S. Huber, A. C. Hocke, B. Opitz, E. Hoffmann, M. Kracht, J. Zerrahn, et al. (2004)
J. Biol. Chem. 279, 53241-53247
   Abstract »    Full Text »    PDF »
ATP-binding Cassette Transporter A1 Contains a Novel C-terminal VFVNFA Motif That Is Required for Its Cholesterol Efflux and ApoA-I Binding Activities.
M. L. Fitzgerald, K.-i. Okuhira, G. F. Short III, J. J. Manning, S. A. Bell, and M. W. Freeman (2004)
J. Biol. Chem. 279, 48477-48485
   Abstract »    Full Text »    PDF »
The Molecular Adapter Carma1 Controls Entry of I{kappa}B Kinase into the Central Immune Synapse.
H. Hara, C. Bakal, T. Wada, D. Bouchard, R. Rottapel, T. Saito, and J. M. Penninger (2004)
J. Exp. Med. 200, 1167-1177
   Abstract »    Full Text »    PDF »
A Novel Ubiquitin-like Domain in I{kappa}B Kinase {beta} Is Required for Functional Activity of the Kinase.
M. J. May, S. E. Larsen, J. H. Shim, L. A. Madge, and S. Ghosh (2004)
J. Biol. Chem. 279, 45528-45539
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Activation of the I{kappa}B Kinase Complex and Nuclear Factor-{kappa}B Contributes to Mutant Huntingtin Neurotoxicity.
A. Khoshnan, J. Ko, E. E. Watkin, L. A. Paige, P. H. Reinhart, and P. H. Patterson (2004)
J. Neurosci. 24, 7999-8008
   Abstract »    Full Text »    PDF »
Signaling to NF-{kappa}B.
M. S. Hayden and S. Ghosh (2004)
Genes & Dev. 18, 2195-2224
   Abstract »    Full Text »    PDF »
The I{kappa}B Kinase (IKK) Inhibitor, NEMO-binding Domain Peptide, Blocks Osteoclastogenesis and Bone Erosion in Inflammatory Arthritis.
S. Dai, T. Hirayama, S. Abbas, and Y. Abu-Amer (2004)
J. Biol. Chem. 279, 37219-37222
   Abstract »    Full Text »    PDF »
Hyperresponse to T-Cell Receptor Signaling and Apoptosis of Id1 Transgenic Thymocytes.
Z. Qi and X.-H. Sun (2004)
Mol. Cell. Biol. 24, 7313-7323
   Abstract »    Full Text »    PDF »

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