Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation.
Canonical and noncanonical nuclear factor kappaB (NF-kappaB) signaling are the two basic pathways responsible for the release of NF-kappaB dimers from their inhibitors. Enhanced NF-kappaB signaling leads to inflammatory and proliferative diseases; thus, inhibitory pathways that limit its activity are critical. Whereas multiple negative feedback mechanisms control canonical NF-kappaB signaling, none has been identified for the noncanonical pathway. Here, we describe a mechanism of negative feedback control of noncanonical NF-kappaB signaling that attenuated the stabilization of NF-kappaB-inducing kinase (NIK), the central regulatory kinase of the noncanonical pathway, induced by B cell-activating factor receptor (BAFF-R) and lymphotoxin beta receptor (LTbetaR). Inhibitor of kappaB (IkappaB) kinase alpha (IKKalpha) was previously thought to lie downstream of NIK in the noncanonical NF-kappaB pathway; we showed that phosphorylation of NIK by IKKalpha destabilized NIK. In the absence of IKKalpha-mediated negative feedback, the abundance of NIK increased after receptor ligation. A form of NIK with mutations in the IKKalpha-targeted serine residues was more stable than wild-type NIK and resulted in increased noncanonical NF-kappaB signaling. Thus, in addition to the regulation of the basal abundance of NIK in unstimulated cells by a complex containing tumor necrosis factor receptor-associated factor (TRAF) and cellular inhibitor of apoptosis (cIAP) proteins, IKKalpha-dependent destabilization of NIK prevents the uncontrolled activity of the noncanonical NF-kappaB pathway after receptor ligation.
Razani
Bahram
B
Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, 609 Charles E. Young Drive East, Los Angeles, CA 90095, USA.
Zarnegar
Brian
B
Ytterberg
A Jimmy
AJ
Shiba
Travis
T
Dempsey
Paul W
PW
Ware
Carl F
CF
Loo
Joseph A
JA
Cheng
Genhong
G
D000818:Animals; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000097782:NF-kappaB-Inducing Kinase
D053265:B-Cell Activation Factor Receptor; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase