Article (Scientific journals)
Noncanonical NF-kappaB Signaling Is Limited by Classical NF-kappaB Activity.
Gray, Carolyn M.; Remouchamps, Caroline; McCorkell, Kelly A. et al.
2014In Science Signaling, 7 (311), p. 13
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Abstract :
[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 :
7
Issue :
311
Pages :
ra13
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 05 March 2015

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