Noncanonical NF-kappaB Signaling Is Limited by Classical NF-kappaB Activity.

[en] Precise regulation of nuclear factor kappaB (NF-kappaB) signaling is crucial for normal immune responses, and defective NF-kappaB activity underlies a range of immunodeficiencies. NF-kappaB is activated through two signaling cascades: the classical and noncanonical pathways. The classical pathway requires inhibitor of kappaB kinase beta (IKKbeta) and NF-kappaB essential modulator (NEMO), and hypomorphic mutations in the gene encoding NEMO (ikbkg) lead to inherited immunodeficiencies, collectively termed NEMO-ID. Noncanonical NF-kappaB activation requires NF-kappaB-inducing kinase (NIK) and IKKalpha, but not NEMO. We found that noncanonical NF-kappaB was basally active in peripheral blood mononuclear cells from NEMO-ID patients and that noncanonical NF-kappaB 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 IKKalpha or IKKbeta. Binding of NEMO to IKKalpha was not required for ligand-dependent stabilization of NIK or noncanonical NF-kappaB signaling. Rather, an intact and functional IKK complex was essential to suppress basal NIK activity in unstimulated cells. Despite interacting with IKKalpha and IKKbeta to form an IKK complex, NEMO mutants associated with immunodeficiency failed to rescue classical NF-kappaB signaling or reverse the accumulation of NIK. Together, these findings identify a crucial role for classical NF-kappaB activity in the suppression of basal noncanonical NF-kappaB signaling.

Disciplines :

Radiology, nuclear medicine & imaging

Author, co-author :

Gray, Carolyn M.

Remouchamps, Caroline ; Université de Liège - ULiège > GIGA-R : Labo of Molecular Immunol. and Signal Transduction

McCorkell, Kelly A.

Solt, Laura A.

Dejardin, Emmanuel ; Université de Liège - ULiège > GIGA-R : Labo of Molecular Immunol. and Signal Transduction

Orange, Jordan S.

May, Michael J.

Language :

English

Title :

Noncanonical NF-kappaB Signaling Is Limited by Classical NF-kappaB Activity.

Publication date :

2014

Journal title :

Science Signaling

ISSN :

1945-0877

eISSN :

1937-9145

Publisher :

American Association for the Advancement of Science, Washington, United States - District of Columbia

Volume :

Issue :

311

Pages :

ra13

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 05 March 2015

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