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Nat Commun. 2015 May 7;6:7068. doi: 10.1038/ncomms8068.

IκBβ enhances the generation of the low-affinity NFκB/RelA homodimer.

Author information

1
1] Signaling Systems Laboratory, University of California, San Diego, 9500 Gilman Dr M/C 0375, La Jolla, California, 92093-0375 [2] The San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Dr M/C 0375, La Jolla, California, 92093-0375 [3] Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr M/C 0375,La Jolla, California, 92093-0375.
2
1] Signaling Systems Laboratory, University of California, San Diego, 9500 Gilman Dr M/C 0375, La Jolla, California, 92093-0375 [2] Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr M/C 0375,La Jolla, California, 92093-0375.
3
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr M/C 0375,La Jolla, California, 92093-0375.
4
1] Signaling Systems Laboratory, University of California, San Diego, 9500 Gilman Dr M/C 0375, La Jolla, California, 92093-0375 [2] The San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Dr M/C 0375, La Jolla, California, 92093-0375 [3] Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr M/C 0375,La Jolla, California, 92093-0375 [4] Department of Microbiology, Immunology and Molecular Genetics (MIMG), Institute for Quantitative and Computational Biosciences (QCB), University of California, Los Angeles, California, 90095.

Abstract

The NFκB family of dimeric transcription factors regulate inflammatory and immune responses. While the dynamic control of NFκB dimer activity via the IκB-NFκB signalling module is well understood, there is little information on how specific dimer repertoires are generated from Rel family polypeptides. Here we report the iterative construction-guided by in vitro and in vivo experimentation-of a mathematical model of the Rel-NFκB generation module. Our study reveals that IκBβ has essential functions within the Rel-NFκB generation module, specifically for the RelA:RelA homodimer, which controls a subset of NFκB target genes. Our findings revise the current dogma of the three classical, functionally related IκB proteins by distinguishing between a positive 'licensing' factor (IκBβ) that contributes to determining the available NFκB dimer repertoire in a cell's steady state, and negative feedback regulators (IκBα and -ɛ) that determine the duration and dynamics of the cellular response to an inflammatory stimulus.

PMID:
25946967
PMCID:
PMC4425231
DOI:
10.1038/ncomms8068
[Indexed for MEDLINE]
Free PMC Article

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