mutation of Ikbkg causes immune deficiency without impairing degradation of IκBÎ

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010, Vol.107 (7), p.3046-3051
• Main Authors: Siggs, Owen M, Berger, Michael, Krebs, Philippe, Arnold, Carrie N, Eidenschenk, Celine, Huber, Christoph, Pirie, Elaine, Smart, Nora G, Khovananth, Kevin, Xia, Yu, McInerney, Gerald, Karlsson Hedestam, Gunilla B, Nemazee, David, Beutler, Bruce
• Format: Article
• Language: English
• Subjects: IKappaB kinase; immunosuppression (physiological); lymph nodes; memory; men; mice; mitogen-activated protein kinase; mutation; null alleles; phosphorylation; T-lymphocytes; Toll-like receptors; transcription factor NF-kappa B
• ISSN: 0027-8424; 1091-6490

Null alleles of the gene encoding NEMO (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 of memory 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.