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

作者：Gray Carolyn M; Remouchamps Caroline; McCorkell Kelly A; Solt Laura A; Dejardin Emmanuel; Orange Jordan S; May Michael J^*

来源：Science Signaling, 2014, 7(311): ra13.

DOI：10.1126/scisignal.2004557

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 beta (IKK beta) 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 IKK alpha, 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 IKK alpha or IKK beta. Binding of NEMO to IKK alpha 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 IKK alpha and IKK beta 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.

• 出版日期2014-2-4