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Generation and Activation of Multiple Dimeric Transcription Factors within the NF-B Signaling System

Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California—San Diego, La Jolla, California 92093-0375

Received 14 August 2007/ Returned for modification 10 October 2007/ Accepted 15 February 2008

The NF-B signaling pathway regulates the activity of multiple dimeric transcription factors that are generated from five distinct monomers. The availabilities of specific dimers are regulated during cell differentiation and organ development and determine the cell's responsiveness to inflammatory or developmental signals. An altered dimer distribution is a hallmark of many chronic diseases. Here, we reveal that the cellular processes that generate different NF-B dimers are highly connected through multiple cross-regulatory mechanisms. First, we find that steady-state expression of RelB is regulated by the canonical pathway and constitutive RelA activity. Indeed, synthesis control of RelB is the major determinant of noncanonical NF-B dimer activation. Second, processing, not synthesis, of p100 and p105 is mechanistically linked via competitive dimerization with a limited pool of RelA and RelB. This homeostatic cross-regulatory mechanism determines the availability of the p50- and p52-containing dimers and also of the noncanonical IB p100. Our results inform a wiring diagram to delineate NF-B dimer formation that emphasizes that inflammatory and developmental signaling cannot be considered separately but are highly interconnected.

Published ahead of print on 25 February 2008.