Crosstalk via the NF-κB signaling system

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Abstract

The nuclear factor kappaB (NF-κB) family of transcription factors consists of 15 possible dimers whose activity is controlled by a family of inhibitor proteins, known as IκBs. A variety of cellular stimuli, many of them transduced by members of the tumor necrosis factor receptor (TNFR) superfamily, induce degradation of IκBs to activate an overlapping subset of NF-κB dimers. However, generation and stimulus-responsive activation of NF-κB dimers are intimately linked via various cross-regulatory mechanisms that allow crosstalk between different signaling pathways through the NF-κB signaling system. In this review, we summarize these mechanisms and discuss physiological and pathological consequences of crosstalk between apparently distinct inflammatory and developmental signals. We argue that a systems approach will be valuable for understanding questions of specificity and emergent properties of highly networked cellular signaling systems.

Introduction

The tumor necrosis factor receptor (TNFR) superfamily comprises more than two dozen members. Their primary physiological functions appear to be in the immune system, both in the development of specialized immune cells and organs, and in the immune response to pathogens. Many TNFR superfamily members and their extracellular ligands have been shown to play critical roles in the organization of the spleen, the development of lymph nodes and thymus, and maturation of T-cells and B-cells within these organs. The lymphotoxin beta receptor (LTβR), for example, is critical for secondary lymphoid organ development, while signaling emanating from BAFFR is important for B-cell survival and maturation. Other TNFR superfamily members are critical for mediating inflammatory responses that may be initiated by pathogen sensing receptors of the TLR superfamily. TNFR superfamily members also play important roles in coordinating innate and adaptive immune responses. For example, two TNF receptors, TNFR1 and TNFR2, mediate the function of the proinflammatory cytokine TNF, and CD40R initiates a powerful B-cell proliferation and activation program upon binding of the ligand CD40L produced by T-cells. Though the distinction between immune development and immune response processes seems intuitive, a variety of observations point towards links between them. One focus of this review will be the signaling crosstalk between the molecular pathways that mediate immune responses and those that mediate immune developmental processes.

The signaling system that controls the activity of nuclear factor kappaB (NF-κB) is responsive to virtually all TNFR superfamily members (Fig. 1). NF-κB activity consists of a family of dimeric transcription factors. Five related mammalian NF-κB proteins, namely RelA/p65, RelB, cRel/Rel, p50 and p52, can potentially form 15 different homo- or heterodimeric complexes [1]. The NF-κB proteins share an approximately 300 amino acid Rel homology region (RHR), which comprises domains for DNA binding, dimerization and nuclear localization. NF-κB dimers bind to the promoters of a variety of genes via a sequence element termed the kappaB (κB) site, which exhibits a loose consensus 5′-GGRNN(WYYCC)-3′ (where R: purine, N: any base, W: adenine or thymine and Y: pyrimidine). Sequence heterogeneity confers specificity to the promoters via differential utilization of specific NF-κB isoforms [1].

Five proteins have also been identified that can inhibit NF-κB activity. These include three inhibitors of NF-κB (IκBs), namely IκBα, -β and -ɛ [2], [3], [4], and two NF-κB precursor proteins, namely nfkb1 p105 and nfkb2 p100. Common to all five NF-κB inhibitors is the ankyrin repeat domain (ARD), which masks NF-κB DNA binding and nuclear translocation sequences [5]. NF-κB activation is achieved through stimulus-responsive proteolysis of the inhibitors. In fact, two mechanisms were originally proposed to account for the NF-κB activation [6]: (a) existence of latent activity bound to a separate inhibitor that releases NF-κB dimer during signaling, and (b) a precursor processing mechanism that generates active NF-κB dimer. The distinction between these two activation mechanisms, as discussed later, continues to be relevant to our current understanding of NF-κB signaling.

Section snippets

Latent NF-κB/RelA:p50 dimer bound to IκBs

The primary mediator of NF-κB function in most cell types is the RelA:p50 dimer. A C-terminal domain of RelA renders this heterodimer a potent transcriptional activator. The detergent deoxycholate was found to liberate κB DNA binding activity in the cytoplasmic extract prepared from the unstimulated cells, confirming the existence of latent NF-κB/RelA:p50 that is bound to inhibitor(s) [7], that were later identified as the three canonical or classical IκBs, IκBα, -β and -ɛ. These inhibitors

Canonical NF-κB activation during immune response

Innate immunity represents a first defense to pathogen infection, followed by adaptive immune responses. Pathogen associated molecular pattern (PAMP) recognition by epithelial or tissue resident hematopoietic cells induces expression of cytokines, which act as mediators of inflammation to recruit phagocytic cells for pathogen clearance. Interestingly, all known PAMPs induce IκB phosphorylation and RelA:p50 activation, and the resulting inflammatory cytokines are also potent inducers of the

Secondary lymphoid organ development via the LTβR

Secondary lymph nodes provide a microenvironment for antigen recognition and lymphocyte maturation during an adaptive immune response. Lymph nodes are located throughout the body to monitor the draining fluids and migrating lymphocytes for pathological changes [29], [30]. The ltbr−/− mice demonstrated that lymphotoxin-β receptor (LTβR) signaling critically regulates lymph node formation [31], [32]. During early embryogenesis, membrane bound LTα1β2 on the hematopoietically derived lymph tissue

A “four IκB” containing mathematical model

Unlike the three canonical IκBs, IκBδ is not degraded in response to IKK2 mediated inflammatory signals, but its expression is induced due to NF-κB-dependent transcriptional activation of nfκb2/p100 [41]. To further address the relationship between canonical and non-canonical signaling, a set of ordinary differential equations that describe synthesis, degradation and molecular interactions of p100 was included into a mathematical model that already accounted for NF-κB activation dynamics in

Non-canonical activation of NF-κB/RelB DNA binding activity

Non-canonical signaling results not only in RelA:p50 activation, but there is significant literature on the activation of the RelB:p52 dimer, which may be slower and more persistent. LTβR stimulation was shown to induce nuclear accumulation of RelB:p52 via the NIK/IKK1 mediated phosphorylation and processing of de novo synthesized, rather than pre-existing p100 protein into p52 [37], [56], [57]. Indeed, a first phase of RelA activity was proposed to induce p100 synthesis to amplify RelB:p52

Concluding remarks

As mouse genetic studies of signaling proteins have yielded surprising phenotypes and thus revealed unexpected functional interdependencies and redundancies, we are forced to confront the interconnectedness of a signaling network that breaks the simplifying assumptions of linear signaling pathways. With a large number of TNFR superfamily members functionally interacting with a complex NF-κB signaling system consisting of 15 possible dimers, a systems biology approach may be called for in

Acknowledgements

In the interest of clarity, we have narrowly focused this review article and apologize for not citing many important contributions in the field. Research on related topics in the Signaling Systems Laboratory was funded by the NIH. We also acknowledge helpful discussions with members of the laboratory during preparation of the manuscript.

Soumen Basak is currently a postdoctoral fellow in the Signaling Systems Laboratory, UCSD. His research interests encompass the functional interactions between different stimuli within the immune system, and how these are mediated through the NF-κB signaling system. Signaling crosstalk is a systems emergent property that can be characterized with interdisciplinary tools, involving biochemistry, genetics and mathematical modeling. He received his graduate training with Dhrubajyoti Chattopadhdyay

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    Soumen Basak is currently a postdoctoral fellow in the Signaling Systems Laboratory, UCSD. His research interests encompass the functional interactions between different stimuli within the immune system, and how these are mediated through the NF-κB signaling system. Signaling crosstalk is a systems emergent property that can be characterized with interdisciplinary tools, involving biochemistry, genetics and mathematical modeling. He received his graduate training with Dhrubajyoti Chattopadhdyay (Calcutta University) on the molecular mechanisms that regulate Chandipura virus replication and gene expression.

    Alexander Hoffmann is assistant professor in the Department of Chemistry and Biochemistry at UCSD. He established the Signaling Systems Laboratory (http://signalingsystems.ucsd.edu) at UCSD in 2003 to study signaling networks with a combination of biochemical, genetic and computational modeling tools. A primary focus is the NF-κB pathway that controls diverse gene expression programs. His graduate training was with Robert G Roeder (Rockefeller University) on the molecular characterization of TFIID and postdoctoral training was with David Baltimore (MIT and Caltech) on the genetic analysis of NF-κB. He is a Hellman Foundation fellow, and an Ellison Foundation investigator in Aging Research.

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