Chapter 9 : The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches

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This chapter reviews the nature of bipartite nuclear factor-κB (NF-κB) regulatory pathways activated in response to monokines produced as a consequence of viral infection, and those involved in mediating RNA viral infection. The chapter discusses work using mRNA profiling studies to determine the genetic networks downstream of NF-κB in response to monokines and RNA virus replication. Inhibition of reactive oxygen species (ROS) formation blocks Ser-276 phosphorylation and NF-κB-dependent gene expression without affecting NF-κB translocation. It was also found that RelA Ser-276 phosphorylation allows complex formation with the cyclin-dependent kinases (CDK)-9/Ccn T1, known as positive transcription elongation factor-b (PTEF-b). Reovirus is a segmented double-stranded RNA (dsRNA) virus that induces cellular apoptosis in an NF-κB-dependent manner. In a study, the tTA-IκB-α Mut cell system was exposed to reovirus for various times from 0 to 10 h in the presence or absence of functional NF-κB signaling. The major pathways are now understood to be composed of bipartite signaling modules whose actions affect nuclear translocation and, separately, transcription factor activation. The chapter also reviews systematic approaches to understanding the signaling pathway, including proteomics, mathematical modeling, real-time imaging, and gene network analyses.

Citation: Brasier A. 2009. The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches, p 119-135. 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.ch9
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Figure 1

The canonical NF-κB activation pathway induced by the TNF-α monokine. A schematic view of the canonical NF-κB signaling pathway coupled to the TNFR. Ligation with TNF-α induces receptor trimerization and recruitment of signaling adaptors. The two modules controlling NF-κB translocation (IKK–IκB-α) and NF-κB activation/phosphorylation (ROS-PKAc) are shown. The sites of the NF-κB–IκB-α and NF-κB–TNFAIP3/A20 negative autoregulatory “feedback loops” are diagrammed.

Citation: Brasier A. 2009. The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches, p 119-135. 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.ch9
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Figure 2

The viral-induced canonical NF-κB activation pathway downstream of the RIG-I/ MAVS complex. Schematic view of the RIG-I/MAVS-induced NF-κB activation pathway and the nuclear translocation (IKK–IκB-α) and activation (TLR3-RelA Ser-276 kinase) modules. Caspase recruitment domains are shown in dark gray; MAVS-TRAF interaction domains are shaded light gray. vRNA, viral (ds) RNA.

Citation: Brasier A. 2009. The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches, p 119-135. 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.ch9
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Figure 3

The viral-induced noncanonical NF-κB activation pathway. Schematic view of the noncanonical and cross-talk pathways leading to RelB•NF-κB2 and RelA•NF-κB1 nuclear translocation. The mechanisms of viral replication coupling to NIK–IKK-α and the role of RelA/RelB phosphorylation have not yet been elucidated.

Citation: Brasier A. 2009. The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches, p 119-135. 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.ch9
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Figure 4

Dynamics of NF-κB: “oscillations.” In certain cells with appropriate cytoplasmic:nuclear volumes, chronic stimulation with TNF-α induces NF-κB oscillatory behavior, where RelA cycles in and out of the nucleus. This diagram shows the control of NF-κB subcellular localization, IKK kinase activity, RelA nuclear abundance, and cytoplasmic IκB-α levels during a single oscillation of the IKK–IκB-α module. (Top) Timing of the TNF-α stimulus.

Citation: Brasier A. 2009. The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches, p 119-135. 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.ch9
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Figure 5

Ingenuity Pathways networks of NF-κB-dependent gene networks. The NF-κB-dependent genes determined from mRNA profiling studies in response to TNF-α, RSV, and reovirus (REO) were mapped onto the IPKB (http://www.ingenuity.com/). Shown are labeled nodes representing individual protein functions and their relationship represented by edges. Nodes are colored by identification, with gray shapes indicating upregulation of the gene in the input dataset. Squares indicate cytokines, circles indicate chemokines, and ovals indicate transcription factors. For the edges, an arrow indicates “acts on”; straight lines indicate binding interactions.

Citation: Brasier A. 2009. The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches, p 119-135. 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.ch9
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