Review Article | Published:

Shaping the nuclear action of NF-κB

Abstract

The NF-κB/REL family of transcription factors pivotally control the inflammatory and immune responses, as well as other genetic programmes that are central to cell growth and survival. The cytoplasmic regulation of NF-κB is well characterized and, recently, significant progress has been made in understanding how its nuclear action is regulated. Post-translational modification of the NF-κB subunits as well as histones surrounding the NF-κB target genes has a key role in this regulation. Here, we review the important advances that constitute this new and exciting chapter in NF-κB biology.

Key Points

  • The nuclear factor (NF)-κB/REL family of transcription factors regulate a diverse range of cellular responses, which include proliferation, differentiation, programmed cell death and tumorigenesis, and they are the 'master regulators' of inflammation and immunity.

  • Classical NF-κB activation involves stimulus-coupled phosphorylation of cytoplasmic IκB inhibitors by IκB kinases (IKK). The IκB inhibitors are targeted to the 26S proteasome allowing the p50/RELA NF-κB complexes to enter the nucleus and stimulate target-gene transcription.

  • A parallel non-classical pathway of REL protein activation has been identified that generates nuclear p52/RELB heterodimers.

  • Post-translational modifications, such as phosphorylation and acetylation, have recently been found to regulate NF-κB transcriptional activity and contribute to shaping the strength and duration of the NF-κB response.

  • The RELA subunit of NF-κB is targeted for stimulus-coupled phosphorylation at different sites by different kinases. RELA phosphorylation is generally associated with enhanced transcriptional activity of NF-κB.

  • RELA is modified by acetylation at key lysine residues. Site-specific acetylation controls different biological functions of NF-κB including DNA binding, transcriptional activity and assembly with IκBα. Deacetylation of RelA promotes IκBα binding and nuclear export of the NF-κB complex, thereby terminating the transcriptional response.

  • Activation of NF-κB-responsive genes also involves multiple modifications of histone proteins surrounding the target genes, so IKK can participate in both the first and second phases of the NF-κB activation response.

  • Analogous to the epigenetic histone code that might regulate gene expression through changes in chromatin structure, a transcription-factor code might exist, in which serial post-translational modifications of the transcription factor can alter its biological function.

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Acknowledgements

L.F.C. is the recipient of an Arthritis Foundation Investigator Award. This work was supported in part by a National Institutes of Health grant to W.C.G., a National Institutes of Health training grant to L.F.C., and by funds from the J. David Gladstone Institutes and Pfizer, Inc. This work also benefited from core facilities provided through the University of California San Francisco-Gladstone Institute for Virology and Immunology Center for AIDS Research. We thank J. Carroll and C. Goodfellow for assistance in the preparation of the figures, S. Ordway and G. Howard for editorial assistance, and R. Givens for administrative support.

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Correspondence to Warner C. Greene.

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Glossary

REL-HOMOLOGY DOMAIN

(RHD). A conserved region of 300 amino acids within the amino-terminal region of all NF-κB/REL-family members. This region is responsible for DNA binding, dimerization and the interaction with IκB-family members.

TRANSACTIVATION DOMAIN

(TAD). A protein domain that is present within transcription factors and that interacts directly with co-activators or components of the general transcription machinery. When tethered to a heterologous DNA-binding domain, this protein domain can stimulate transcription.

CO-ACTIVATOR

A protein that forms a 'bridge' between the transcriptional activators and general transcription factors that promote gene expression.

PROTEASOME

A large protein complex that is responsible for degrading intracellular proteins that have been targeted for destruction, usually by the addition of ubiquitin polymers.

ANKYRIN REPEAT

A protein–protein-interaction motif that comprises repeated modules of approximately 33 amino acids. Ankyrin repeats are found in proteins with diverse functions including transcription factors, cell-cycle regulators, ion transporters and signal transducers. The IκB-family proteins and some NF-κB/REL-family proteins contain ankyrin-repeat domains.

PHOSPHOACCEPTOR

An amino acid such as serine, threonine or tyrosine that can be phosphorylated by kinases.

LIPOPOLYSACCHARIDE

(LPS). A lipid-containing polysaccharide that is an endotoxin and an important group-specific antigen and that is derived from the cell wall of Gram-negative bacteria.

SIGNALSOME

A multiprotein kinase complex that mediates stimulus-coupled phosphorylation of two regulatory serine residues in the IκBs. This complex contains IKK1/IKKα, IKK2/IKKβ and NEMO/IKKγ. IKK1/IKKα and IKK2/IKKβ are the catalytic subunits of the kinase complex, whereas NEMO/IKKγ is a key non-enzymatic regulatory subunit.

HISTONE DEACETYLASE

(HDAC). An enzyme that removes the acetyl groups from core histones or certain transcription factors; its activity contributes to transcriptional regulation and cell-cycle progression through alterations in chromatin structure or transcription-factor activity.

HEPATIC STELLATE CELLS

The principal producers of extracellular matrix in the fibrotic liver that contribute to hepatic inflammation through the secretion of chemokines and the recruitment of leukocytes.

HISTONE ACETYLTRANSFERASE

(HAT). An enzyme that adds acetyl groups to histones. Many HATs function as transcriptional co-activators.

CHROMOSOMAL-REGION MAINTENANCE-1

A nuclear-export protein also known as exportin-1, the activity of which is specifically inhibited by leptomycin B.

HETEROCHROMATIN

A condensed form of chromatin in which the degree of compaction is similar to that of mitotic chromosomes. It is usually found around the centromere.

HISTONE TAIL

The amino-terminus of histone polypeptides that protrudes out of the nucleosome. It is subject to different covalent modifications, including phosphorylation, acetylation, methylation, ubiquitylation and ADP-ribosylation. These modifications affect chromatin structure and contribute to the regulation of transcription.

IMMEDIATE-EARLY GENES

Genes that are induced rapidly and transiently and do not require new protein synthesis. They are directly connected to intracellular signalling systems and control the transcription of other genes.

HISTONE CODE

Post-translational modifications of histone tails that involve characteristic clusters of modifications, including acetylation, phosphorylation, ubiquitylation, methylation and ADP-ribosylation that combine to create an epigenetic mechanism for the regulation of gene expression.

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Further reading

Figure 1: Targeting of RELA by multiple protein kinases induced by distinct stimuli.
Figure 2: Differential acetylation regulates distinct functions of RELA.
Figure 3: Phosphorylation and acetylation of RELA and histone tails regulate NF-κB-target-gene expression.