A novel mutation in the Nfkb2 gene generates an NF-kappa B2 "super repressor".
The noncanonical NF-kappaB pathway regulates the development and function of multiple organs and cell lineages. We have generated mice harboring a novel mutation in Nfkb2 that prevents the processing of the inhibitory precursor, p100, into the active subunit, p52. Mutant mice express a complex phenotype with abnormalities in a variety of tissues, and with a spectrum that is more severe than in mice carrying a targeted deletion of Nfkb2. Signaling through the noncanonical pathway is ablated due to the absence of p52, resulting in disorganized splenic architecture and disrupted B cell development. The inhibitory precursor form of NF-kappaB2 interacts with RelA, preventing activation of RelA dimers in response to both canonical and noncanonical stimuli, which in combination with p52 deficiency, results in defective lymph node formation and bone homeostasis. These findings demonstrate a key role for NF-kappaB2 in the regulation of RelA activation and suggest overlap in the function of NF-kappaB members in canonical and noncanonical pathway signaling.
Tucker
Elena
E
St Vincent's Institute, Fitzroy, Victoria, Australia.
O'Donnell
Kristy
K
Fuchsberger
Martina
M
Hilton
Adrienne A
AA
Metcalf
Donald
D
Greig
Kylie
K
Sims
Natalie A
NA
Quinn
Julian M
JM
Alexander
Warren S
WS
Hilton
Douglas J
DJ
Kile
Benjamin T
BT
Tarlinton
David M
DM
Starr
Robyn
R
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000502:physiology*; D010010:Osteoclasts / Q000276:immunology; D010375:Pedigree; D013601:T-Lymphocytes / Q000276:immunology; D051996:Transcription Factor RelA / Q000502:physiology
D052003:NF-kappa B p52 Subunit; C498207:Nfkb2 protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA