A fourth IkappaB protein within the NF-kappaB signaling module.
Inflammatory NF-kappaB/RelA activation is mediated by the three canonical inhibitors, IkappaBalpha, -beta, and -epsilon. We report here the characterization of a fourth inhibitor, nfkappab2/p100, that forms two distinct inhibitory complexes with RelA, one of which mediates developmental NF-kappaB activation. Our genetic evidence confirms that p100 is required and sufficient as a fourth IkappaB protein for noncanonical NF-kappaB signaling downstream of NIK and IKK1. We develop a mathematical model of the four-IkappaB-containing NF-kappaB signaling module to account for NF-kappaB/RelA:p50 activation in response to inflammatory and developmental stimuli and find signaling crosstalk between them that determines gene-expression programs. Further combined computational and experimental studies reveal that mutant cells with altered balances between canonical and noncanonical IkappaB proteins may exhibit inappropriate inflammatory gene expression in response to developmental signals. Our results have important implications for physiological and pathological scenarios in which inflammatory and developmental signals converge.
Basak
Soumen
S
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Kim
Hana
H
Kearns
Jeffrey D
JD
Tergaonkar
Vinay
V
O'Dea
Ellen
E
Werner
Shannon L
SL
Benedict
Chris A
CA
Ware
Carl F
CF
Ghosh
Gourisankar
G
Verma
Inder M
IM
Hoffmann
Alexander
A
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002461:Cell Line, Transformed; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics* / Q000378:metabolism; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D046911:Macromolecular Substances; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C498207:Nfkb2 protein, mouse; C496559:CHUK protein, human