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A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha.


ABSTRACT: 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.

SUBMITTER: Siggs OM 

PROVIDER: S-EPMC2840324 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

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A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha.

Siggs Owen M OM   Berger Michael M   Krebs Philippe P   Arnold Carrie N CN   Eidenschenk Celine C   Huber Christoph C   Pirie Elaine E   Smart Nora G NG   Khovananth Kevin K   Xia Yu Y   McInerney Gerald G   Karlsson Hedestam Gunilla B GB   Nemazee David D   Beutler Bruce B  

Proceedings of the National Academy of Sciences of the United States of America 20100128 7


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 f  ...[more]

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