The NF-kappaB family of transcription factors and its regulation

Abstract

Nuclear factor-kappaB (NF-kappaB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-kappaB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-kappaB proteins (IkappaBs), which retain inactive NF-kappaB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-kappaB activation converge on the IkappaB kinase (IKK) complex, which is responsible for IkappaB phosphorylation and is essential for signal transduction to NF-kappaB. Additional regulation of NF-kappaB activity is achieved through various post-translational modifications of the core components of the NF-kappaB signaling pathways. In addition to cytosolic modifications of IKK and IkappaB proteins, as well as other pathway-specific mediators, the transcription factors are themselves extensively modified. Tremendous progress has been made over the last two decades in unraveling the elaborate regulatory networks that control the NF-kappaB response. This has made the NF-kappaB pathway a paradigm for understanding general principles of signal transduction and gene regulation.

Figure 1.

NF-κB stimuli and target genes. NF-κB acts as a central mediator of immune and inflammatory responses, and is involved in stress responses and regulation of cell proliferation and apoptosis. The respective NF-κB target genes allow the organism to respond effectively to these environmental changes. Representative examples are given for NF-κB inducers and κB-dependent target genes.

Figure 2.

Members of the NF-κB, IκB, and IKK protein families. The Rel homology domain (RHD) is characteristic for the NF-κB proteins, whereas IκB proteins contain ankyrin repeats (ANK) typical for this protein family. The precursor proteins p100 and p105 can therefore be assigned to and fulfill the functions of both the NF-κB and IκB protein families. The domains that typify each protein are indicated schematically. CC, coiled-coil; DD, death domain; GRR, glycine-rich region; HLH, helix-loop-helix; IKK, IκB kinase; LZ, leucine-zipper; NBD, NEMO binding domain; PEST, proline-, glutamic acid-, serine-, and threonine-rich region; TAD, transactivation domain; ZF, zinc finger.

Figure 3.

Canonical and non-canonical signaling to NF-κB. The canonical pathway is, e.g., induced by TNFα, IL-1, or LPS and uses a large variety of signaling adaptors to engage IKK activity. Phosphorylation of serine residues in the signal responsive region (SRR) of classical IκBs by IKKβ leads to IκB ubiquitination and subsequent proteosomal degradation. This results in release of the NF-κB dimer, which can then translocate to the nucleus and induce transcription of target genes. The non-canonical pathway depends on NIK (NF-κB-inducing kinase) induced activation of IKKα. IKKα phosphorylates the p100 NF-κB subunit, which leads to proteosomal processing of p100 to p52. This results in the activation of p52-RelB dimers, which target specific κB elements.