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

Journal article

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.

Authors: Siggs, O; Berger, M; Krebs, P; Arnold, C; Eidenschenk, C

• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 107
• Issue: 7
• Pages: 3046-3051
• Publication date: 2010-02-01
• DOI: 10.1073/pnas.0915098107
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: Mice, Transgenic; Lymph Nodes; T-Lymphocytes, Regulatory; Male; Flow Cytometry; I-kappa B Kinase; Immunologic Deficiency Syndromes; Ethylnitrosourea; Mice; Mutation; Cytokines; Mutagenesis; Signal Transduction; Animals; Intracellular Signaling Peptides and Proteins; Nitric Oxide; Toll-Like Receptors; Blotting, Western