Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 7, Pages 3046-3051Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0915098107
Keywords
mutagenesis; N-ethyl-nitrosourea; nuclear factor-kappa B essential modulator; p65; Toll-like receptor
Categories
Funding
- National Institutes of Health [AI070167, RO1GM44809]
- National Institute of Allergy and Infectious Diseases Broad Agency Announcement [HHSN272200700038C]
- Bill and Melissa Gates Foundation
- Swiss National Science Foundation
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Null alleles of the gene encoding NEMO (NF-kappa B 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 I kappa B 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-kappa B p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond I kappa B alpha degradation, and offers a biochemical explanation for rare immune deficiencies in man.
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