The Journal of Experimental Medicine
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Published online 2 October 2006 doi:10.1084/jem.20061166
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 11, 2413-2418
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BRIEF DEFINITIVE REPORT

 Rescue of TRAF3-null mice by p100 NF-{kappa}B deficiency

Jeannie Q. He1, Brian Zarnegar1, Gagik Oganesyan1,2, Supriya K. Saha1,2, Soh Yamazaki1, Sean E. Doyle1, Paul W. Dempsey1, and Genhong Cheng1,3

1 Department of Microbiology, Immunology, and Molecular Genetics, 2 Medical Scientist Training Program, and 3 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095

CORRESPONDENCE Genhong Cheng: genhongc{at}microbio.ucla.edu

Proper activation of nuclear factor (NF)–{kappa}B transcription factors is critical in regulating fundamental biological processes such as cell survival and proliferation, as well as in inflammatory and immune responses. Recently, the NF-{kappa}B signaling pathways have been categorized into the canonical pathway, which results in the nuclear translocation of NF-{kappa}B complexes containing p50, and the noncanonical pathway, which involves the induced processing of p100 to p52 and the formation of NF-{kappa}B complexes containing p52 (Bonizzi, G., and M. Karin. 2004. Trends Immunol. 25:280–288). We demonstrate that loss of tumor necrosis factor (TNF) receptor–associated factor 3 (TRAF3) results in constitutive noncanonical NF-{kappa}B activity. Importantly, TRAF3–/– B cells show ligand-independent up-regulation of intracellular adhesion molecule 1 and protection from spontaneous apoptosis during in vitro culture. In addition, we demonstrate that loss of TRAF3 results in profound accumulation of NF-{kappa}B–inducing kinase in TRAF3–/– cells. Finally, we show that the early postnatal lethality observed in TRAF3-deficient mice is rescued by compound loss of the noncanonical NF-{kappa}B p100 gene. Thus, these genetic data clearly demonstrate that TRAF3 is a critical negative modulator of the noncanonical NF-{kappa}B pathway and that constitutive activation of the noncanonical NF-{kappa}B pathway causes the lethal phenotype of TRAF3-deficient mice.

J.Q. He and B. Zarnegar contributed equally to this work.


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