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

IκB Kinase (IKK)α is required for activation of an alternative NF-κB signaling pathway based on processing of the NF-κB2/p100 precursor protein, which associates with ReIB 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 IKKκ dependence of the induction of these genes in response to engagement of the lymphotoxin β receptor (LTβR). 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-κB signaling pathway. We identified in the IKKα-dependent promoters a novel type of NF-κB-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.