Rescue of TRAF3-null mice by p100 NF-kappa B deficiency.
Proper activation of nuclear factor (NF)-kappaB 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-kappaB signaling pathways have been categorized into the canonical pathway, which results in the nuclear translocation of NF-kappaB complexes containing p50, and the noncanonical pathway, which involves the induced processing of p100 to p52 and the formation of NF-kappaB 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-kappaB 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-kappaB-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-kappaB p100 gene. Thus, these genetic data clearly demonstrate that TRAF3 is a critical negative modulator of the noncanonical NF-kappaB pathway and that constitutive activation of the noncanonical NF-kappaB pathway causes the lethal phenotype of TRAF3-deficient mice.
He
Jeannie Q
JQ
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Zarnegar
Brian
B
Oganesyan
Gagik
G
Saha
Supriya K
SK
Yamazaki
Soh
S
Doyle
Sean E
SE
Dempsey
Paul W
PW
Cheng
Genhong
G
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D005804:Genes, Lethal; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011499:Protein Processing, Post-Translational; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency* / Q000235:genetics*
D052003:NF-kappa B p52 Subunit; D048008:TNF Receptor-Associated Factor 3