THE NF-κB AND IκB PROTEINS: New Discoveries and Insights

TL;DR: The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases.

Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

Summary

1. INTRODUCTION

• Ten years ago Sen & Baltimore (1) first described NF-κB as a B cell nuclear factor that bound a site in the immunoglobulin κ enhancer.
• These and other reviews (6–12) offer a thorough background on NF-κB. NF-κB1 and NF-κB2 are proteins that contain both the Rel homology domain and ankyrin repeats.

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• Processing of these proteins (see below) leads to the production of the p50 and p52 subunits.
• More examples of biologically relevant targets for the different dimers and of possible roles in gene-specific transcription are needed.
• AND FUNCTION OF NF-κB 653 or RelA-containing dimers are likely not to be strongly regulated by IκB.
• Recently, the 46-kDa IκBβ was purified to homogeneity, and a cDNA clone was derived (26).

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• Like IκBα, IκBβ preferentially interacts with dimers that contain c-Rel or RelA.
• Two forms of RNA are detected (the smaller RNA is not large enough to encode the described protein), with the larger form expressed in heart and skeletal muscle but not in brain, lung, liver, or kidney.
• The IκB-R protein inhibits the DNA binding activity of the p50/RelA dimer and the p50 homodimer but not that of the RelA homodimer, suggesting a preferential interaction with the 50-kDa NF-κB1 subunit.
• Another cDNA clone encoding a protein (IκBL) with homology to IκB family members has been reported (28).
• The protein contains two complete and one partial ankyrin repeat and is encoded by a gene in the major histocompatibility complex.

3. STRUCTURAL AND EVOLUTIONARY STUDIES

• ON NF-κB 3.1 Crystallography of NFκB1 Bound to DNA.
• The overall structure is striking and butterfly-like (see Figure 2).
• The general relatedness of the RHD in each of the immediate NF-κB family members strongly suggests that a similar overall structure will constitute the DNA binding and dimerizations domains of each family member.

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• Consistent with previous deletion studies, it is proposed that amino acids in and around the NLS will constitute a composite surface for interaction with IκB.
• The mechanism accounting for nuclear levels of c-Rel-p50 is not fully clear but may be explained by significantly increased instability of IκBα and by increased transcription of the c-Rel gene (43, 44).
• Thus, NF-κB may have both positive and negative effects on apoptosis in B cells.

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• These factors include p50 homodimers, the p50-RelA heterodimer, and c-Rel.
• Additionally, both c-Rel and RelA interact with the TATA-binding protein (TBP), and the C-terminus of RelA interacts with the basal factor TFIIB (56 and references therein).
• An extensive list of genes regulated by NF-κB is provided in previous reviews (4, 5).
• VCAM-1 is also implicated in other cellular processes because it is expressed in the developing central nervous system, in human lymph nodes, and on bone marrow stromal cells.

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• HMG I(Y) stimulates the binding of NF-κB to PRDII by binding to the A/T-rich core sequence.
• NF-κB is strongly implicated in the transcriptional regulation of several cytokine and growth factor genes, including IL-2, IL-6, IL-8, and G-CSF.
• Thus p50 homodimers likely negatively regulate expression of the IFNβ gene.
• These studies demonstrate an important role for RelB in immune function and in the differentiation of dendritic cells and thymic medullary epithelial cells.

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• Family and, therefore, that there is no simple redundancy within the NF-κB/Rel proteins.
• 4.3 RELA The RelA (p65) null mice exhibit a dramatic phenotype–embryonic lethality apparently due to widespread apoptosis within the liver (87).
• Additionally, the c-Rel deficient mice displayed deficient immunoglobulin production in unchallenged animals, and T cell–dependent humoral immune responses to antigenic challenge were also impaired.
• The loss of IκBα leads to the nuclear localization of NF-κB in most cell types, most prominently in the spleen and thymus.

5. MECHANISMS FOR THE ACTIVATION AND

• Enormous progress has been made toward identifying the mechanisms whereby NF-κB is activated to move into the nucleus in response to numerous stimuli.
• Specific molecular events involved in this activation are now well described and offer insights into a fascinating control mechanism.
• Based on studies showing that IκBα is intrinsically unstable when not associated with NF-κB, phosphorylation of IκBα was generally thought to lead to its dissociation from NF-κB, which resulted in proteolysis (9).
• Recent experiments have offered a different interpretation.

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• Like IκBα, IκBβ is targeted for degradation in response to the inducers LPS and IL-1.
• Presumably these two lysines are the targets for uibiquitination.
• Additional roles for constitutive phosphorylation of IκBαmay include regulation of the stability of free IκB or assembly with NF-κB subunits.

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• Inducers lead to the degradation of the p105 precursor protein with the appearance of the p50 form (4, 5).
• It was therefore proposed that nuclear NF-κB caused the transcriptional activation of the IκBα gene.
• Evidence for this is that IκBβ is targeted for degradation with slower kinetics than IκBα and that there is apparent inducer specificity in the targeting of the two IκB forms.

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• It would be interesting to map the potential phosphorylation sites on IκBα targeted by dsRNA-activated kinase.
• Additionally, a kinase reportedly associated with NF-κB/IκB complexes also appears to phosphorylate the NF-κB subunits (117).
• In addition, FK506, an inhibitor of calcineurin, blocks the activation of c-Rel in B and T cells (118).
• The generation of ceramide in response to TNF or IL-1 may be critical in initiating the events leading to NF-κB activation via degradation of IκBα (see 120 and references therein).

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• Interestingly, it has been proposed that Ras and Raf, but not Map, kinases are involved in this activation (131).
• 7 Activation of NF-κB by Viral Proteins Many viral gene products activate NF-κB.
• It is unlikely that significant progress will be made on the NF-κB signaling pathway(s) until research proceeds directly downstream from known receptors and directly upstream from the final phosphorylated substrates (IκB and NF-κB subunits).
• Glucocorticoids reportedly inhibit NF-κB by two mechanisms.

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• CsA blocks the activation of NF-κB in response to the engagement of the T cell receptor (75).
• NO inhibits the activation of NF-κB in response to treatment with TNFα (161).
• Agonists that increase cellular cAMP levels may be important modulators of immune responses.
• Since NF-κB activates transcription of the iNOS gene (see above), activation of NF-κB by LPS may play a role in the development of septic shock.

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• Oncogene family; (ii) the NF-κB2 gene and the Bcl-3 gene are translocated in certain lymphomas; (iii) NF-κB is activated in quiescent fibroblasts in response to serum growth factors; (iv) NF-κB is activated by viral transforming proteins (Tax and LMP-1, for example; see above); and (v) exposure of cells to IκBα antisense results in oncogenic transformation (174).
• A role for NF-κB/Rel proteins in human cancer presumably would involve transcriptional functions, such as the upregulation of the c-myc gene (see above).
• Recently, a truncated form of IκBα (presumably functioning as a “super-repressor” based on the loss of the critical N-terminal serines) was shown to protect AT cells from killing by ionizing radiation and to correct the defect in DNA synthesis (179).
• An additional homology exists with the yeast RAD3 protein, which is involved in cell cycle control.
• It is unclear whether NF-κB is activated in other cell types of AT patients and, if so, whether NF-κB may contribute to the neurological or immunological deficiencies.

7. SUMMARY

• Ten years of research on NF-κB has led to a much greater understanding of the role of this family of transcription factors and their inhibitors in immunity, inflammation, and cell growth and development.
• The functional roles of IκBα and IκBβ, as well as potential new forms of inhibitors, need to be clearly delineated.
• Clarification of the mechanisms through which dysregulation of NF-κB contributes to disease is clearly needed.

ACKNOWLEDGMENTS

• I gratefully acknowledge past and present lab members for their work and enthusiasm.
• A specific inhibitor of the NF-κB transcription factor, also known as IκB.

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• Characterization of elements determining the dimerization properties of RelB and p50.
• Differential interactions of Rel-NF-κB complexes with IκBα determine pools of constitutive and inducible NF-κB activity.
• The PEST-like sequence of IκBα is responsible for inhibition of DNA binding but not for cytoplasmic retention of c-Rel or RelA homodimers.
• Lawrence R, Chang LJ, Siebenlist U, Bressler P, Sonenshein G. 1994.

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• Function of NF-κB/Rel binding sites in the MHC class II invariant chain promoter is dependent on cell-specific binding of different NF-κB/Rel subunits.
• Activation of NF-κB requires proteolysis of the inhibitor IκBα: signal-induced phosphorylation of IκBα alone does not release active NF-κB. Proc. Natl. Acad. Sci. USA 92:552–56 95. DiDonato J, Mercurio F, Karin M. 1995.

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• ΚB sitedependent induction of gene expression by diverse inducers of NF-κB requires Raf-1. J. Biol.
• Evidence in support of a role for human T-cell leukemia virus type I tax in activating NF-κB via stimulation of signaling pathways.

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• Pression of NF-κB by activated glucocorticoid receptors.
• Role of transcriptional activation of IκBα in mediation of immunosuppression by glucocorticoids.
• Induction and stabilization of IκBα by nitric oxide mediates inhibition of NF-κB. J. Biol.

Full text

February 20, 1996 10:47 Annual Reviews BALDCHPT AR11-25
Annu. Rev. Immunol. 1996. 14:649–81
Copyright
c

1996 by Annual Reviews Inc. All rights reserved
THE NF-κB AND IκB PROTEINS: New
Discoveries and Insights
Albert S. Baldwin, Jr.
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and
Molecular Biology, and Department of Biology, University of North Carolina,
Chapel Hill, North Carolina 27599
KEY WORDS: NF-κB/Rel transcription factors, IκB, inflammatory cytokines, B and T cell
activation, signal transduction
ABSTRACT
The transcription factor NF-κB has attracted widespread attention among re-
searchers in many fields based on the following: its unusual and rapid regulation,
the wide range of genes that it controls, its central role in immunological pro-
cesses, the complexity of its subunits, and its apparent involvement in several
diseases. A primary level of control for NF-κB is through interactions with an
inhibitor protein called IκB. Recent evidence confirms the existence of multiple
forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can
beactivatedbyexposureof cells to LPS or inflammatory cytokines such as TNF or
IL-1, viral infection or expression of certain viral gene products, UV irradiation,
B or T cell activation, and by other physiological and nonphysiological stim-
uli. Activation of NF-κB to move into the nucleus is controlled by the targeted
phosphorylation and subsequent degradation of IκB. Exciting new research has
elaborated several important and unexpected findings that explain mechanisms
involved in the activation of NF-κB. In the nucleus, NF-κB dimers bind to target
DNA elements and activate transcription of genes encoding proteins involved
with immune or inflammation responses and with cell growth control. Recent
data provide evidence that NF-κB is constitutively active in several cell types,
potentially playing unexpected roles in regulation of gene expression. In addi-
tion to advances in describing the mechanisms of NF-κB activation, excitement
in NF-κB research has been generated by the first report of a crystal structure for
one form of NF-κB, the first gene knockout studies for different forms of NF-κB
649
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650 BALDWIN
and of IκB, and the implications for therapies of diseases thought to involve the
inappropriate activation of NF-κB.
1. INTRODUCTION
Ten years ago Sen & Baltimore (1) first described NF-κB as a B cell nuclear
factor that bound a site in the immunoglobulin κ enhancer. In the same year,
these researchers also showed (2) that NF-κB could be activated in other cells
by exposure to stimuli such as phorbol esters, and that this activation was
independent of protein synthesis. In the next few years, functional NF-κB
binding sites were found in the promoters of many genes, most of which were
not B cell specific. These promoter/enhancers included IL-2, IL-6, GM-CSF,
ICAM-1, and class I MHC. Typically, NF-κB binding sites serve as inducible
transcriptional regulatory elements that respond to immunological stimuli such
as TNF, IL-1, LPS, or T cell activators. However, the range of inducers is
not limited to these mediators of immune function; other stimuli such as UV
irradation, growthfactors, and viralinfection also activateNF-κB. Thebasis for
the latent nature of NF-κB and for its inducibility is the association of NF-κB
with a cytoplasmic inhibitory protein called IκB (3). The release from IκB
allows for the extraordinarily rapid appearance of NF-κB in the nucleus. Thus,
certain genes regulated by NF-κB can be transcriptionally activated within
minutes following exposure to the relevant inducer.
Ten years after its discovery, the NF-κB and IκB field remains a lively
arena for research. Five members of the mammalian NF-κB/Rel proteins have
been identified that are characterized by the Rel homology domain (RHD), an
N-terminal region of approximately 300 amino acids. These proteins are mem-
bers of an evolutionarily conserved family of proteins, some of which regulate
body pattern formation and immune function in insects. Consistent with a
complex system for regulatory control, there are multiple forms of IκB pro-
teins characterized by several copies of the so-called ankyrin repeat. Recent
research has elaborated several of the critical aspects of signaling that medi-
ate NF-κB translocation in response to inducer. Gene knockout studies firmly
establish a role for NF-κB in immune function and eliminate any models that
claim simple redundancy for the functions of the different NF-κB/Rel pro-
teins. Regulation of NF-κB by the network of regulatory cytokines and other
immune function modulators is now well established and is growing in com-
plexity. Additionally, the gene deletion studies as well as other approaches
provide support for a role of the NF-κB proteins in functions beyond immunity
and inflammatory responses, including roles in liver development and in several
disease processes.
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REGULATION AND FUNCTION OF NF-κB 651
Two recent Annual Reviews chapters (4, 5) have covered NF-κB in great
detail through much of 1993. These and other reviews (6–12) offer a thorough
background on NF-κB. The aim of this review is to provide coverage of some
of the significant advances in NF-κB over the last two years. Many reports
involving NF-κB have appeared during this time; due to space limitations, it is
impossible for this review to cover all of these important results. In addition,
reviews reference previous work where appropriate.
2. THE NF-κB/REL AND IκB PROTEINS
Presently, five members of the mammalian NF-κB/Rel familyhave been cloned
and characterized. These are c-Rel, NF-κB1 (p50/p105), NF-κB2 (p52/p100),
RelA (p65), and RelB (4–12). The Rel homology domain (RHD; see Figure 1)
found in each of these proteins functions in DNA binding, dimerization, and
interactions with IκB forms. Two of the proteins, NF-κB1 (p105) and NF-κB2
(p100),containmultiplecopiesoftheso-calledankyrinrepeatat theirC-termini.
Figure 1 The NF-κB/Rel and IκB families of proteins. The NF-κB/Rel family is characterized
by the presence of the Rel homology domain. The IκB proteins have multiple copies of the ankyrin
repeat. NF-κB1 and NF-κB2 are proteins that contain both the Rel homology domain and ankyrin
repeats. Dorsal, Dif, and Cactus are Drosophila proteins. See text for discussion.
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652 BALDWIN
Processing of these proteins (see below) leads to the production of the p50
and p52 subunits. The p100 and p105 proteins serve regulatory functions in
the cell (see below) and should not be considered exclusively as precursor
forms. Furthermore, some evidence suggests that alternative splicing of the
p105 mRNA leads to the translation of additional forms of this protein (13).
2.1 NF-κB Is a Dimer of Variable Subunits
Active, DNA-binding NF-κB is a dimer. Classic NF-κB (the dimer of p50 and
RelA) has been the most intensively studied, although many other homo- and
heterodimers have been described. Certain dimers apparently do not exist; for
example, RelB dimerizes only with p50 or p52 (14). Each of the various NF-κB
dimers may exhibit distinct properties. For example, binding site preference
has been identified for certain dimers. Classic NF-κB binds the sequence 5
0
GGGRNNYYCC 3
0
, whereas the RelA/c-Rel dimer binds to a sequence (5
0
HGGARNYYCC 3
00
; H indicates A, C or T; R is purine; Y is pyrimdine) (15).
Selective binding sites for RelA/c-Rel heterodimers are found in the promoters
of several inducible genes, including those encoding tissue factor and GM-CSF
(15); the RelA/c-Rel dimer is inducible by LPS or by cytokines. The ability of
differentdimers torecognize slightly different DNA targetsincreases theability
of NF-κB subunits to differentially regulate gene expression. More examples
of biologically relevant targets for the different dimers and of possible roles
in gene-specific transcription are needed. Additional differences between the
NF-κB dimers include cell type specificity, differential subcellular localization,
differential interactions with forms of IκB, and differential activation (4, 5).
2.2 Dimers of NF-κB Are Targeted by Monomers of IκB
Initial characterization of cytoplasmic NF-κB revealed that it was associated
with either of two forms of IκB–IκBα or IκBβ (4, 5). The cloning of IκBα
(16, 17) allowed progress to be made at several levels. First, it was established
that IκBα contains ankyrin repeats (Figure 1). Second, IκBα retains NF-κB
in the cytoplasm through masking of the nuclear localization sequences (4, 5,
9). Third, the identification of IκB as an ankyrin repeat containing protein
allowed for the prediction that the function of the homologous ankyrin repeats
in the precursors of the p50 subunit (NF-κB1) and of the p52 subunit (NF-
κB2) was as an intramolecular IκB (see 4, 5). Thus precursors dimerize with
another member of the Rel familythrough the RHD, and the C-terminal ankyrin
repeat regionfunctions to retain this dimer in the cytoplasm (also see discussion
below). Finally, IκBα exhibited homology with a protein encoded by the gene
bcl-3 found to be translocated in certain lymphomas (see 4, 5, and below).
Immunoprecipitation studies indicate that IκBα is associated predominantly
with c-Rel- and RelA-containing dimers. Studies indicate that certain non-Rel
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REGULATION AND FUNCTION OF NF-κB 653
or RelA-containing dimers are likely not to be strongly regulated by IκB. For
example, IκBα exhibits a lower affinity for RelB-p52 heterodimers than for
RelB-p50 dimers (18), and this likely contributes to constitutive nuclear levels
oftheformerfactor. RelBcomplexesinlymphoidcellsmayhavealoweraffinity
for IκBα due either to a modification to RelB or to a cell-specific cofactor (19).
IκB interaction with NF-κB subunits occurs with residues in the Rel homology
domain, and presumed contacts in or around the nuclear localization sequence
(NLS) appear to play critical functional roles in inhibiting nuclear localization
of NF-κB (4, 9). In addition, data indicate that a single IκB targets the NF-κB
dimer (20, 21).
IκBα can be divided into three structural domains: a 70-amino-acid N-ter-
minal region, a 205-amino-acid internal region that is composed of ankyrin
repeats, and a C-terminal 42-amino-acid region that contains a so-called PEST
region. Mutationand protease sensitivity studies indicate that deletion of theN-
terminalor C-terminal regiondoes notinhibit the abilityof IκBα to interactwith
NF-κB (20, 22). However, deletion of the C-terminus does block the ability
of IκBα to inhibit DNA binding of NF-κB (20). Mutations within the ankyrin
repeat block interactions with NF-κB (4, 5). The discussion below describes
important regulatory aspects of the N- and C-terminal regions of IκBα.
Other forms of IκB include the precursors NF-κB1 and NF-κB2, IκBγ (an
independent protein derived from a unique transcript from NF-κB1) which
appears to be limited only to mouse B cells, and Bcl-3 (Figure 1; see 4, 5). The
recently cloned IκBβ is discussed below. Precursor proteins can dimerize with
other NF-κB subunits to form dimer molecules that cannot bind to DNA and
that cannot translocate into the nucleus (4, 5). NF-κB2 precursor p100 or its
C-terminus can form a trimeric complex with a dimer of NF-κB subunits (23,
24), suggesting a different mechanism whereby precursors function in an IκB-
like role. Bcl-3 is nuclear in its localization and functions as a transcriptional
activator with the p50 or p52 homodimer. Thus the ability of Bcl-3 to interact
with these forms of NF-κB results in transcriptional activation rather than an
inhibitionofnucleartransportoraninhibitionofDNAbinding(4, 5). Consistent
withtheseresults is theobservation (25) thattheNLSregionofp50 is apparently
not contacted by Bcl-3, in contrast to the interactions between IκBα and NF-κB
subunits.
2.3 IκBβ Appears To Have Properties Distinct from IκBα
As stated above, purification of NF-κB revealed that two forms of IκB were as-
sociated with NF-κB dimers. One form, IκBα, is described above and has been
intensively studied. Recently, the 46-kDa IκBβ was purified to homogeneity,
and a cDNA clone was derived (26). Like IκBα,IκBβcontains ankyrin re-
peats (Figure 1) and is associated with NF-κB forms in the cytoplasm of various
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Frequently asked questions

Q1. What are the contributions mentioned in the paper "The nf-κb and iκb proteins: new discoveries and insights" ?

The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. In addition to advances in describing the mechanisms of NF-κB activation, excitement in NF-κB research has been generated by the first report of a crystal structure for one form of NF-κB, the first gene knockout studies for different forms of NF-κB 649 0732-0582/96/0410-0649 $ 08. 00 A nn u. R ev. Recent data provide evidence that NF-κB is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression. 

Q2. What is the role of IB in reestablishing cytoplasmic pools?

The rapid reaccumulation of IκBα following its loss is apparently important in reestablishing cytoplasmic pools of NF-κB/IκB complexes. 

Q3. What is the role of phosphatases in the activation of NF-B?

Phosphatases likely play an important role in the activation of NF-κB, either regulating kinase pathways that may control the signal transduction pathway or by directly dephosphorylating IκB. 

Q4. What is the idea that NF-B could be modified?

One idea is that NF-κB that is associated with IκBβ would be modified (possibly by phosphorylation) so that it could not be targeted for inhibition by IκBα. 

Q5. What is the role of vascular adhesion molecule-1 in the developing nervous system?

Experimentation has revealed that vascular adhesion molecule-1 (VCAM-1) is expressed in the developing central nervous system on neuroepithelial cells (52), which are precursors of glial cells and neurons. 

Q6. What is the role of tepoxalin in NF-B?

An example is tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenease, which functions to inhibit NF-κB induction by several inducers in multiple cell types (150). 

Q7. What is the role of NF-B/Rel proteins in human cancer?

A role for NF-κB/Rel proteins in human cancer presumably would involve transcriptional functions, such as the upregulation of the c-myc gene (see above). 

Q8. What is the role of NF-B in the regulation of cell growth?

Although NF-κB/Rel proteins are strongly implicated in the regulation of genes involved in the immune system and in inflammation, these transcription factors also regulate genes involved in control of cell growth. 

Q9. What is the role of bZIP proteins in the regulation of IL-8?

Interactions between NF-κB proteins and bZIP proteins are implicated in the inducible regulation of the genes encoding IL-8, E-selectin, and G-CSF, A nn u. Rev . 

Q10. What is the role of NF-B in cell adhesion molecules?

The group of genes encoding cell adhesion molecules has been studied extensively for an involvement of NF-κB in their regulation. 

Q11. What mechanism would prevent IB from inhibiting NF-B?

Mechanisms that would prevent IκBα, which rapidly reaccumulates following induction, from inhibiting the IκBβ-released NF-κB have been proposed. 

Q12. What is the mechanism accounting for nuclear levels of c-Rel-p50?

The mechanism accounting for nuclear levels of c-Rel-p50 is not fully clear but may be explained by significantly increased instability of IκBα and by increased transcription of the c-Rel gene (43, 44).