A mutation of Ikbkg causes immune deficiency without impairing degradation of IκBα

Owen M. Siggs, Michael Berger, Philippe Krebs, Carrie N. Arnold, Celine Eidenschenk, Christoph Huber, Elaine Pirie, Nora G. Smart, Kevin Khovananth, Yu Xia, Gerald McInerney, Gunilla B. Karlsson Hedestam, David Nemazee, Bruce Beutler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Null alleles of the gene encodingNEMO(NF-κB 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 ofmemory and regulatory T cells, and Ig production, but did not cause ectodermal dysplasia. Degradation of IκBα, 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-κB p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond IκBα degradation, and offers a biochemical explanation for rare immune deficiencies in man.

Original languageAmerican English
Pages (from-to)3046-3051
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
StatePublished - 16 Feb 2010
Externally publishedYes


  • Mutagenesis
  • N-ethyl-nitrosourea
  • Nuclear factor-κB essential modulator
  • Toll-like receptor
  • p65


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