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

Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3046-51. doi: 10.1073/pnas.0915098107. Epub 2010 Jan 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cytokines / metabolism
  • Ethylnitrosourea
  • Flow Cytometry
  • I-kappa B Kinase / metabolism
  • Immunologic Deficiency Syndromes / genetics*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / immunology
  • Lymph Nodes / growth & development
  • Male
  • Mice
  • Mice, Transgenic
  • Mutagenesis
  • Mutation / genetics*
  • Nitric Oxide / metabolism
  • Signal Transduction / genetics*
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory
  • Toll-Like Receptors / metabolism


  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • NEMO protein, mouse
  • Toll-Like Receptors
  • Nitric Oxide
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ethylnitrosourea