A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha.
Null alleles of the gene encoding NEMO (NF-kappaB essential modulator) are lethal in hemizygous mice and men, whereas hypomorphic alleles typically cause a syndrome of immune deficiency and ectodermal dysplasia. Here we describe an allele of Ikbkg in mice that impaired Toll-like receptor signaling, lymph node formation, development of memory and regulatory T cells, and Ig production, but did not cause ectodermal dysplasia. Degradation of IkappaB alpha, which is considered a primary requirement for NEMO-mediated immune signaling, occurred normally in response to Toll-like receptor stimulation, yet ERK phosphorylation and NF-kappaB p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond IkappaB alpha degradation, and offers a biochemical explanation for rare immune deficiencies in man.
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Owen M
OM
Siggs
Michael
M
Berger
Philippe
P
Krebs
Carrie N
CN
Arnold
Celine
C
Eidenschenk
Christoph
C
Huber
Elaine
E
Pirie
Nora G
NG
Smart
Kevin
K
Khovananth
Yu
Y
Xia
Gerald
G
McInerney
Gunilla B
GB
Karlsson Hedestam
David
D
Nemazee
Bruce
B
Beutler
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D005038:Ethylnitrosourea; D005434:Flow Cytometry; D051550:I-kappa B Kinase / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D008198:Lymph Nodes / Q000254:growth & development; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory; D051193:Toll-Like Receptors / Q000378:metabolism
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D051193:Toll-Like Receptors; D009569:Nitric Oxide; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D005038:Ethylnitrosourea