Lymphotoxin β Receptor Induces Sequential Activation of Distinct NF-κB Factors via Separate Signaling Pathways*

By Jürgen R. Müller, U. Siebenlist. Journal of Biological Chemistry, 2003

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Lymphotoxin β receptor (LTβR)-induced activation of NF-κB in mouse embryo fibroblasts was mediated by the classical pathway and by an alternative or second pathway. The classical pathway involved the IκB kinase (IKK)β- and IKKγ-dependent degradation of IκBα and resulted in the rapid but transient activation of primarily RelA-containing NF-κB dimers. The alternative or second pathway proceeded via NF-κB-inducing kinase (NIK)-, IKKα-, and protein synthesis-dependent processing of the inhibitory NF-κB2 p100 precursor protein to the p52 form and resulted in a delayed but sustained activation of primarily RelB-containing NF-κB dimers. This second pathway was independent of the classical IKK complex, which is governed by its central IKKγ regulatory subunit. The sequential engagement of two distinct pathways, coupled with the negative feedback inhibition of RelA complexes by NF-κB-induced resynthesis of IκBα, resulted in a pronounced temporal change in the nature of the NF-κB 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-κB activity in mouse embryo fibroblasts in response to LTβR stimulation. Based on the phenotype of mice deficient in various components of the LTβR-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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/acfe0f7fc478623680415eb28fba3e04c6fb2653

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