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Sci. Signal., 4 February 2014
Vol. 7, Issue 311, p. ra13
[DOI: 10.1126/scisignal.2004557]


Noncanonical NF-{kappa}B Signaling Is Limited by Classical NF-{kappa}B Activity

Carolyn M. Gray1, Caroline Remouchamps2, Kelly A. McCorkell1, Laura A. Solt3, Emmanuel Dejardin2, Jordan S. Orange4,5, and Michael J. May1,6*

1 Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA.
2 Laboratory of Molecular Immunology and Signal Transduction, The University of Liège-GIGA Research, 4000 Liège, Belgium.
3 Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
4 Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX 77030, USA.
5 Department of Pediatrics, Texas Children’s Hospital, Houston, TX 77030, USA.
6 The Mari Lowe Center for Comparative Oncology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.

Abstract: Precise regulation of nuclear factor {kappa}B (NF-{kappa}B) signaling is crucial for normal immune responses, and defective NF-{kappa}B activity underlies a range of immunodeficiencies. NF-{kappa}B is activated through two signaling cascades: the classical and noncanonical pathways. The classical pathway requires inhibitor of {kappa}B kinase β (IKKβ) and NF-{kappa}B essential modulator (NEMO), and hypomorphic mutations in the gene encoding NEMO (ikbkg) lead to inherited immunodeficiencies, collectively termed NEMO-ID. Noncanonical NF-{kappa}B activation requires NF-{kappa}B–inducing kinase (NIK) and IKKα, but not NEMO. We found that noncanonical NF-{kappa}B was basally active in peripheral blood mononuclear cells from NEMO-ID patients and that noncanonical NF-{kappa}B signaling was similarly enhanced in cell lines lacking functional NEMO. NIK, which normally undergoes constitutive degradation, was aberrantly present in resting NEMO-deficient cells, and regulation of its abundance was rescued by reconstitution with full-length NEMO, but not a mutant NEMO protein unable to physically associate with IKKα or IKKβ. Binding of NEMO to IKKα was not required for ligand-dependent stabilization of NIK or noncanonical NF-{kappa}B signaling. Rather, an intact and functional IKK complex was essential to suppress basal NIK activity in unstimulated cells. Despite interacting with IKKα and IKKβ to form an IKK complex, NEMO mutants associated with immunodeficiency failed to rescue classical NF-{kappa}B signaling or reverse the accumulation of NIK. Together, these findings identify a crucial role for classical NF-{kappa}B activity in the suppression of basal noncanonical NF-{kappa}B signaling.

* Corresponding author. E-mail: maym{at}

Citation: C. M. Gray, C. Remouchamps, K. A. McCorkell, L. A. Solt, E. Dejardin, J. S. Orange, M. J. May, Noncanonical NF-{kappa}B Signaling Is Limited by Classical NF-{kappa}B Activity. Sci. Signal. 7, ra13 (2014).

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