Selective Inhibition of NF-
B Activation by a Peptide That Blocks the Interaction of NEMO with the IB 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)-
B by proinflammatory stimuli leads to increased expression of genes involved in inflammation. Activation of NF-B requires the activity of an inhibitor of B (IB)-kinase (IKK) complex
containing two kinases (IKK
and IKK
) and the regulatory protein
NEMO (NF-B essential modifier). An amino-terminal -helical region
of NEMO associated with a carboxyl-terminal segment of IKK and
IKK 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-B activation and NF-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-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
