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A mutation of Ikbkg causes immune deficiency without impairing degradation of IB
Owen M. Siggsa,
Michael Bergera,
Philippe Krebsa,
Carrie N. Arnolda,
Celine Eidenschenka,
Christoph Huberb,
Elaine Piriea,
Nora G. Smarta,
Kevin Khovanantha,
Yu Xiaa,
Gerald McInerneyc,
Gunilla B. Karlsson Hedestamc,
David Nemazeeb, and
Bruce Beutlera,1
Departments of aGenetics and bImmunology, The Scripps Research Institute, La Jolla, CA 92037; and cDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Contributed by Bruce Beutler, December 30, 2009 (sent for review December 17, 2009)
Abstract:
Null alleles of the gene encoding NEMO (NF-B essential modulator)are lethal in hemizygous mice and men, whereas hypomorphic allelestypically cause a syndrome of immune deficiency and ectodermaldysplasia. Here we describe an allele of Ikbkg in mice thatimpaired 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 IB, whichis considered a primary requirement for NEMO-mediated immunesignaling, occurred normally in response to Toll-like receptorstimulation, yet ERK phosphorylation and NF-B p65 nuclear translocationwere severely impaired. This selective loss of function highlightsthe immunological importance of NEMO-regulated pathways beyondIB degradation, and offers a biochemical explanation for rareimmune deficiencies in man.
Author contributions: O.M.S. and B.B. designed research; O.M.S.,M.B., P.K., C.A., C.E., C.H., E.P., K.K., and Y.X. performedresearch; G.M., G.B.K.H., and D.N. contributed new reagents/analytictools; O.M.S. and B.B. analyzed data; and O.M.S., N.G.S., andB.B. wrote the paper.
1To whom correspondence should be addressed. E-mail: bruce{at}scripps.edu.
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B
B 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 I
, 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-
