Trends in Immunology
Volume 29, Issue 10, October 2008, Pages 469-478
Journal home page for Trends in Immunology

Review
New insights into NF-κB regulation and function

https://doi.org/10.1016/j.it.2008.07.003Get rights and content

NF-κB (nuclear factor-κB) transcription factors have multiple critical roles in the regulation of immune responses. In unstimulated cells, NF-κB proteins are sequestered in the cytoplasm by IκB inhibitory proteins. Various immune stimuli induce the IκB kinase (IKK) to phosphorylate IκBs, triggering their ubiquitination and proteasomal degradation, which permits nuclear translocation of associated NF-κB subunits and activation of NF-κB target genes. Recent studies have highlighted the importance of dynamic ubiquitination-deubiquitination events in regulating this canonical NF-κB signaling pathway. Ubiquitination additionally plays critical roles in activation of the noncanonical pathway that regulates NF-κB via signal-induced processing of NF-κB2 p100. New research has also identified several novel regulatory proteins that control the transcriptional activity of nuclear NF-κB.

Introduction

NF-κB (nuclear factor-κB) regulates genes involved at multiple stages of immune responses, including innate immune cell activation, inflammation, dendritic cell maturation and lymphocyte activation. NF-κB activation is tightly controlled by canonical and atypical pathways that regulate proteolysis of IκB (an inhibitor of NF-κB) and IκB-related proteins (Box 1; Figure 1). Because such basic knowledge of NF-κB has been discussed previously 1, 2, this review will instead focus on new insights gained through recent studies.

Section snippets

Regulation of canonical NF-κB signaling by ubiquitination and deubiquitination

Protein ubiquitination plays a critical role in NF-κB activation. Initially shown to mediate proteasomal degradation of IκBs and processing of NF-κB precursors, ubiquitination is now known to also serve as a nondegradative mechanism for activation of the canonical NF-κB pathway (Box 2). This latter function involves the addition of lysine 63 (K63)-linked ubiquitin chains to specific target proteins.

Noncanonical pathway of NF-κB activation

Processing of p100 and inducible degradation of p105 represent two major atypical pathways of NF-κB activation, with the former being known as the noncanonical NF-κB pathway (Figure 1a). Because p100 and p105 function as both NF-κB precursor proteins and IκB-like molecules (Box 1), their processing and degradation play important roles in mediating NF-κB signaling. The regulation of p105-specific pathway has been thoroughly discussed in a previous review [1], and this section focuses on the

RelA phosphorylation

Posttranslational modification of Rel subunits and their association with other nuclear proteins are critical to regulate the transcriptional activity and specificity of NF-κB dimers (see Refs. 2, 48 for recent reviews). For example, RelA phosphorylation on S276 promotes its interaction with the histone acetyltransferases CBP (CREB-binding protein) and p300 while displacing repressive histone deacetylase (HDAC) proteins [49] (Figure 3). The physiological significance of RelA S276

Concluding remarks

It has now been > 20 years since the original identification of NF-κB as a regulator of κB light chain expression in B cells. Nevertheless, NF-κB is still a major area of research and serves as a paradigm for a signaling pathway that is regulated by ubiquitination. The importance of NF-κB in inflammation, autoimmunity and cancer is clearly established, and there has been a considerable effort by the pharmaceutical industry to develop IKK inhibitors to treat these diseases. However, such

Acknowledgements

Work performed in the authors’ laboratory is supported by the University of Texas MD Anderson Cancer Center, and National Institutes of Health Grants R01 AI064639, R01 AI057555, and R01 CA94922 (to S.C.S.) and UK Medical Research Council (to S.C.L.). We apologize to those investigators whose work was not cited because of space limitations.

Glossary

ABIN
A20-binding inhibitor of NF-κB
BAFFR
B cell–activating factor receptor
CBP
CREB-binding protein
CDK
cyclin-dependent kinase
ChIp
chromatin immunoprecipitation
c-IAP
cellular inhibitor of apoptosis
CYLD
cylindromatosis
DUB
deubiquitinating enzyme
ECSSOCS1
ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1
HDAC
histone deacetylase
IKK
IκB kinase
IκB
inhibitor of NF-κB
LTßR
lymphotoxin β receptor
MAP3K
MAP kinase kinase kinase
NF-κB
nuclear factor-κB
NIK
NF-κB–inducing kinase
RANK
receptor activator of NF-κB
RIP1

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