Lymphotoxin beta receptor induces sequential activation of distinct NF-kappa B factors via separate signaling pathways.
Lymphotoxin beta receptor (LTbetaR)-induced activation of NF-kappaB in mouse embryo fibroblasts was mediated by the classical pathway and by an alternative or second pathway. The classical pathway involved the IkappaB kinase (IKK)beta- and IKKgamma-dependent degradation of IkappaBalpha and resulted in the rapid but transient activation of primarily RelA-containing NF-kappaB dimers. The alternative or second pathway proceeded via NF-kappaB-inducing kinase (NIK)-, IKKalpha-, and protein synthesis-dependent processing of the inhibitory NF-kappaB2 p100 precursor protein to the p52 form and resulted in a delayed but sustained activation of primarily RelB-containing NF-kappaB dimers. This second pathway was independent of the classical IKK complex, which is governed by its central IKKgamma regulatory subunit. The sequential engagement of two distinct pathways, coupled with the negative feedback inhibition of RelA complexes by NF-kappaB-induced resynthesis of IkappaBalpha, resulted in a pronounced temporal change in the nature of the NF-kappaB activity during the course of stimulation. Initially dominant RelA complexes were replaced with time by RelB complexes. Therefore, the alternative activation path mediated by processing of p100 was necessary for sustained NF-kappaB activity in mouse embryo fibroblasts in response to LTbetaR stimulation. Based on the phenotype of mice deficient in various components of the LTbetaR-induced activation of p100 processing, we conclude that this pathway is critically involved in the function of stromal cells during the generation of secondary lymphoid organ microarchitectures.
Müller
Jürgen R
JR
Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Siebenlist
Ulrich
U
D000818:Animals; D002478:Cells, Cultured; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D053259:Lymphotoxin beta Receptor; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D053259:Lymphotoxin beta Receptor; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D014157:Transcription Factors; D000097782:NF-kappaB-Inducing Kinase; C505699:Ltbr protein, mouse; C000606205:Nfkbia protein, mouse; C497594:Relb protein, mouse; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse