Inhibitor of KappaB
The transcriptional factor NF-κB – a key regulator of cellular events such as cell growth, immune response, and cell survival – was first identified by Dr. David Baltimore’s group (Sen and Baltimore 1986). Inhibitor of kappaB (IκB) can form a complex with NF-κB and control these events. IκB family proteins harbor an ankyrin (ANK) repeat domain, a core motif of NF-κB binding, which was first identified in the cell-cycle gene sequences of yeast and Drosophila in 1987 (Breeden and Nasmyth 1987). IκB family members have been found to have conserved ANK repeat domains, including β-strand and α-helix repeat sequences. On the basis of extensive studies, nine IκB family proteins harboring ANK repeats have been identified, and these IκB proteins are classified into two groups according to their localization in the cytosol or nucleus.
IκB Family Proteins Control NF-κB Signaling
Prototypical IκB Family Proteins
IκB-α-deficient mice were first generated in 1995. These mice exhibited severe runting, skin defects, and death within 8 days (Beg et al. 1995). The deficiency of IκB-α was found to lead to constitutive NF-κB activation and high expression levels of NF-κB target genes, including MIP-2 and VCAM-1. Thus, IκB-α plays an important role in maintaining homeostasis through the control of NF-κB activation.
The second member of IκB family proteins to be identified, IκB-β, can also associate with NF-κB through six ANK repeat domains and control NF-κB transcriptional activities (Zabel and Baeuerle 1990). Furthermore, lipopolysaccharide (LPS) stimulation can induce the degradation of IκB-β (Thompson et al. 1995). IκB-α and IκB-β have similar inhibitory effects against NF-κB signaling; however, IκB-β does not have a positive feedback mechanism like IκB-α (induction, binding, export) (Thompson et al. 1995). Furthermore, IκB-β-deficient mice can grow without any disorders or inflammation and do not have constitutive NF-κB activation.
Atypical IκB Family Proteins
Nuclear IκB family proteins have a nuclear localization signal and localize only in the nucleus. The most classic nuclear IκB family protein, Bcl-3, was identified in chromosome 19 in chronic lymphocytic leukemia (Ohno et al. 1990). Bcl-3 has seven ANK repeat domains (Fig. 2), and it forms a complex with NF-κB (p50 subunit) and removes p50 from its DNA-binding site (Franzoso et al. 1993). Bcl-3 ChIP sequence experiments have shown that Bcl-3 can be enriched near the p50-binding site (Jackman et al. 2012). Thus, Bcl-3 might control transcription in cooperation with the NF-κB subunit p50.
Bcl-3-deficient mice were first generated in 1997, and they demonstrated normal growth without any disorders or inflammation (Franzoso et al. 1997). In another study, Bcl-3-deficient mice were found to be less sensitive to dextran-sodium sulfate–induced colitis (Massoumi et al. 2006). Bcl-3 deficiency increases influences UVB-induced apoptosis of the skin. In macrophages, Bcl-3 deficiency leads to the production of large amounts of IL-10 in response LPS stimulation. Interestingly, IL-10 stimulation in macrophages induces Bcl-3 expression, and it negatively regulates LPS-induced TNF-α expression (Kuwata et al. 2003).
IκBNS-deficient mice grow for over 6 months without any disorders or inflammation. In macrophages, IκBNS deficiency leads to high levels of IL-6 in response to LPS stimulation. Therefore, IκBNS-deficient mice have a high sensitivity to LPS-induced endotoxin shock. Another report showed that IκBNS-deficient mice are resistant to experimental autoimmune encephalomyelitis, and that they have low levels of Th17 cell differentiation (Kobayashi et al. 2014). A master regulator of Th17, RORγt, is upregulated by NF-κB signaling. However, IκBNS-deficient T cells show low RORγt expression even in the presence of TGF-β+IL-6 stimulation. Thus, IκBNS in T cells might control NF-κB activity and RORγt expression.
NF-κB signaling plays crucial roles in many cellular events via gene regulation. IκB family proteins are major signaling molecules that control NF-κB signaling. They all have ANK repeat domains and are able to form complexes with NF-κB. Initially, prototypical (cytosolic) IκB family proteins control NF-κB signaling. Subsequently, regulation by nuclear IκB family proteins follows. Importantly, nuclear IκB family proteins can bind to DNA and control gene regulation by NF-κB. However, each nuclear IκB family protein has different target genes and different roles in transcriptional activity. Thus, understanding of the NF-κB signaling pathway is important for understanding many cellular events, including cell survival, development, and homeostasis.
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