30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology

Abstract

NF-κB was discovered 30 years ago as a rapidly inducible transcription factor. Since that time, it has been found to have a broad role in gene induction in diverse cellular responses, particularly throughout the immune system. Here, we summarize elaborate regulatory pathways involving this transcription factor and use recent discoveries in human genetic diseases to place specific proteins within their relevant medical and biological contexts.

Keywords: I-κB; NF-κB; Rel; gene regulation; genetic disease; genomics; human gene; immunity; lymphocyte; transactivator.

Figure 1

The NF-κB paradigm of timely and flexible biochemical control of cell behavior.

Figure 2

A. Rel homology domain proteins in the NF-κB protein family and the v-Rel oncoprotein. The N-terminal regions of REL family proteins share the Rel homology domain (RHD), which has amino acid similarity to the product of the v-rel oncogene from the Reticuloendotheliosis virus REV-T and a nuclear localization sequence (NLS). RelB has a leucine zipper (LZ) and RelA, RelB, and c-Rel, harbor a transactivation domain (TAD). p105 and p100 have 5–7 tandem ankyrin repeats (AnkR) and a death domain (DD). Regulatory phosphorylation sites (P) and ubiquitination sites (Ub) are shown. B. Inhibitors of NF-κB (IκB) family of proteins. The eight described IκBs are characterized by their 5–7 tandem ankyrin repeats (AnkR) which mediate binding to NF-κB dimers. The N-terminal regions of the classical IκBs (IκBα, IκBβ, IκBε) contain two serine residues (P), which permit the accelerated ubiquitination (Ub) and degradation of the protein when phosphorylated. BCL3 has similar modification residues but IκBζ and IκBNS do not. The C-terminal regions of p105 and p100 function as IκBs for their linked RHD even before processing by forming large complexes with Rel proteins, including p50 and p52. PEST: Region rich in the amino acids proline, glutamic acid, serine, and threonine. DD: death domain. C. Structure of the IκB:NF-κB latent complex (PBD 1NFI). Ribbon diagram of the crystal structure of the isolated complex including IκBα (blue), showing its anchor and repeat domain (ARD) and PEST sequence rich in the amino acids proline, glutamic acid, serine, and threonine that acts as a signal for protein degradation, p50 (red), and the RelA (green), inter-domain linker, and N-terminal domain (NTD). D. IKK complex. Shown are the components of the IKK complex including two kinases: IKKα, IKKβ, and the non-enzymatic subunit NEMO. CC1: Coiled-coil domain 1; CC2: Coiled-coil domain 2; LZ: Leucine zipper; Zn: Zinc-finger; Kinase: Kinase domain; HLH: Helix-loop-helix region; NBD: NEMO-binding domain. Regulatory phosphorylation sites (P) and ubiquitination sites (Ub) are shown. The number of amino acids (aa) of each protein is shown at right. Adapted from (Hayden and Ghosh, 2008, 2012).

Figure 3. The major monogenic diseases in the core pathways of both the classical (CP) and alternative (AP) pathways of NF-κB signaling

Color coded boxes indicate the main feature of diseases.