Activation of IKKα target genes depends on recognition of specific κB binding sites by RelB:p52 dimers

Abstract

IkappaB Kinase (IKK)alpha is required for activation of an alternative NF-kappaB signaling pathway based on processing of the NF-kappaB2/p100 precursor protein, which associates with RelB in the cytoplasm. This pathway, which activates RelB:p52 dimers, is required for induction of several chemokine genes needed for organization of secondary lymphoid organs. We investigated the basis for the IKKalpha dependence of the induction of these genes in response to engagement of the lymphotoxin beta receptor (LTbetaR). Using chromatin immunoprecipitation, we found that the promoters of organogenic chemokine genes are recognized by RelB:p52 dimers and not by RelA:p50 dimers, the ubiquitous target for the classical NF-kappaB signaling pathway. We identified in the IKKalpha-dependent promoters a novel type of NF-kappaB-binding site that is preferentially recognized by RelB:p52 dimers. This site links induction of organogenic chemokines and other important regulatory molecules to activation of the alternative pathway.

Transcriptional regulation via the NF-κB signaling module

“…Although the intertwined dimer has low affinity and is unstable, such interactions may occur transiently within the dynamic molecular events of gene regulation. Intriguingly, RelB has been reported to have both positive and negative transcriptional activities (Saccani et al, 2003;Bonizzi et al, 2004;Jacque et al, 2005), but the molecular basis for alternate activities remains unknown.…”

“…This may correlate with the distinct physiological functions in inflammation and immune signaling versus development and homeostasis of secondary lymphoid structures or control of bone homeostasis. Although the focus of past studies has been the activation of the noncanonical pathway-specific RelB dimer (Dejardin et al, 2002;Bonizzi et al, 2004), it is of interest to determine whether temporal control of NF-kB may play a role in distinguishing the developmental from the inflammatory gene expression programs.…”

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…One example of the second mechanism is a variation of the kB site which preferentially binds RelB : p52 heterodimers. 23 Another example involves the c-Rel subunit of NF-kB, which appears to recognize a broader range of kB sites with high affinity in comparison to dimers containing p65. 24 While the DNA-contacting residues of c-Rel and p65 appear to be identical, the broader range of high-affinity interactions by c-Rel homodimers is suggested to arise from unique residues present in the Rel homology region of c-Rel.…”

Crosstalk via the NF-κB signaling system

“…Important lymphoid chemokine genes, such as BLC and SLC, were shown to be RelB target genes (Basak et al, 2008;Schneider et al, 2004) via a proposed variant kappaB site that recruits RelB-but not RelA-containing dimers upon LTβR stimulation (Bonizzi et al, 2004). Homozygous knockin mice expressing a non-activatable IKK1 variant (ikk1 AA/AA ) show impaired lymphoid organogenesis (Senftleben et al, 2001) due to stromal cell defects (Bonizzi et al, 2004).…”