Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers.
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.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Giuseppina
G
Bonizzi
Magali
M
Bebien
Dennis C
DC
Otero
Kirsten E
KE
Johnson-Vroom
Yixue
Y
Cao
Don
D
Vu
Anil G
AG
Jegga
Bruce J
BJ
Aronow
Gourisankar
G
Ghosh
Robert C
RC
Rickert
Michael
M
Karin
D048868:Adaptor Proteins, Signal Transducing; D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase; D053259:Lymphotoxin beta Receptor; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C504650:Psip1 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; C497594:Relb protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051841:Transcription Factor RelB; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse