Selective Inhibition of NF-κB Activation by a Peptide That Blocks the Interaction of NEMO with the IκB Kinase Complex

TLDR

NF‑κB activation by proinflammatory stimuli drives expression of inflammatory genes and requires the IKK complex composed of IKKα, IKKβ, and the regulatory protein NEMO. The study aims to develop drugs that target the NEMO‑binding domain (NBD) to block proinflammatory activation of the IKK complex while preserving basal NF‑κB activity. The NBD is an amino‑terminal α‑helical region of NEMO that associates with the carboxyl‑terminal segments of IKKα and IKKβ. A cell‑permeable NBD peptide disrupted NEMO–IKK association, suppressed cytokine‑induced NF‑κB activation and target gene expression, and reduced inflammatory responses in two acute inflammation mouse models.

Abstract

Activation of the transcription factor nuclear factor (NF)–κB by proinflammatory stimuli leads to increased expression of genes involved in inflammation. Activation of NF-κB requires the activity of an inhibitor of κB (IκB)-kinase (IKK) complex containing two kinases (IKKα and IKKβ) and the regulatory protein NEMO (NF-κB essential modifier). An amino-terminal α-helical region of NEMO associated with a carboxyl-terminal segment of IKKα and IKKβ 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-κB activation and NF-κB–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-κB activity.