Chapter 8 : The Nuclear Factor-κB Transcription Factor Pathway

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Nuclear factor (NF)-κB activating signals, which are discussed in this chapter, induce phosphorylation of I κB proteins, leading to their ubiquitination and proteasome-mediated degradation. Nuclear translocation of the subunits, however, may not be sufficient for transcriptional activation. NF-κB complexes induce expression of key tumor necrosis factor-α (TNF-α) target genes involved in the inflammatory responses, including leukocyte adhesion molecules and chemokines. Phosphorylation at a single key residue (Ser-276) by protein kinase A enhances RelA interaction with the coactivator CREB-binding protein (CBP), resulting in enhanced transcriptional activation potential. NF-κB is a key mediator of inflammatory cytokineinduced responses. The pathway through which TNF-α induces NF-κB activation is among the most well studied in higher eukaryotes. Absence of RelA results in massive hepatocyte apoptosis during embryogenesis, resulting in embryonic lethality. Studies of mice deficient in the NF-κB RelA subunit provided the first direct evidence of a role for NF-κB in inhibiting apoptosis. The NF-κB transcription factors play key functions in many aspects of the antiviral response. Respiratory syncytial virus (RSV) is a member of the paramyxovirus family that causes acute lower respiratory tract infections, which are characterized by high expression of proinflammatory cytokines and chemokines. Virus induction of the interferon (IFN)-β gene is one of the most studied transcriptional systems in mammals. In the heart, however, NF-κB is important for inducing IFN-β expression and therefore in limiting viral replication. Similarly disparate functions for NF-κB also come into play during induction of virus-induced inflammatory and adaptive immune responses.

Citation: Beg A, Wang X. 2009. The Nuclear Factor-κB Transcription Factor Pathway, p 107-118. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch8
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Figure 1

Mammalian NF-κB/Rel and IκB family proteins. The mammalian NF-κB family comprises five members: RelA/p65, cRel, RelB, p100/p52, and p105/p50. They have a structurally conserved amino-terminal Rel homology region, which contains functional domains responsible for dimerization and DNA binding. RelA/p65, cRel, and RelB also have nonhomologous carboxy-terminal transactivation domains. p100 and p105 have carboxy-terminal ankyrin repeats that are homologous to IκB family proteins. p50 and p52 proteins are generated by proteolytic processing of p105 and p100, respectively. IκB family proteins, which are featured by ankyrin repeats, contain IκB-α, IκB-β, IκB-γ, IκB-ε, IκB-ζ (also known as MAIL and INAP), Bcl-3, p105, and p100. IκB-α, IκB-β, and IκB-ε are prototypical IκBs that retain NF-κB proteins in the cytoplasm. Unprocessed p100 and p105 also function as inhibitors of NF-κB. IκB-γ is identical to the carboxy-terminal region of p105 and specifically inhibits p50-containing NF-κB dimers. p105, IκB-γ, and prototypical IκBs (IκB-α and IκB-β) use a similar mechanism to bind but a different mechanism to regulate the subcellular localization of NF-κB. In contrast, Bcl-3 interacts specifically with p50 and p52 homodimers and can induce expression of NF-κB-regulated genes. Similar to Bcl-3, IκB-ζ also functions as an activator of gene expression by specific association with p50.

Citation: Beg A, Wang X. 2009. The Nuclear Factor-κB Transcription Factor Pathway, p 107-118. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch8
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Image of Figure 2
Figure 2

NF-κB activation pathways during viral infection. NF-κB can be activated by many stimuli, including bacterial and viral products, inflammatory cytokines, and antigen receptors. NF-κB plays vital roles in mediating intracellular responses to pathogens that are recognized by pattern recognition receptors (PRRs) such as TLRs. Bacterial product LPS or RSV F protein is recognized by the cell surface-expressed TLR4. Viral single-stranded RNA (ssRNA) and viral DNA can be recognized by TLR7 and TLR9, respectively, which are expressed in the endosomal compartment. Active virus replication-generated viral doublestranded RNA (dsRNA) and viral DNA are sensed by intracellular PRRs RIG-I/MDA-5 and DAI (DNA-dependent activator of IFN regulatory factors), respectively, in the cytoplasm. PRR engagement by its ligand results in activation of IKK complex, composed of kinases IKK-α and IKK-β and the regulatory subunit IKK-γ (also known as NEMO). IκB-α and IκB-β proteins are phosphorylated by the activated IKK complex. Phosphorylated IκBs are then ubiquitinated by β-TrCP (transducin repeat-containing protein), which targets it for degradation by the proteasome. This releases NF-κB dimers from cytoplasmic NF-κB/IκB complexes and allows them to translocate to the nucleus and activate target gene expression.

Citation: Beg A, Wang X. 2009. The Nuclear Factor-κB Transcription Factor Pathway, p 107-118. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch8
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