Rescue of TRAF3-null mice by p100 NF-κB deficiency

Abstract

Proper activation of nuclear factor (NF)-κB 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-κB signaling pathways have been categorized into the canonical pathway, which results in the nuclear translocation of NF-κB complexes containing p50, and the noncanonical pathway, which involves the induced processing of p100 to p52 and the formation of NF-κB 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-κB 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-κB-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-κB p100 gene. Thus, these genetic data clearly demonstrate that TRAF3 is a critical negative modulator of the noncanonical NF-κB pathway and that constitutive activation of the noncanonical NF-κB pathway causes the lethal phenotype of TRAF3-deficient mice. JEM © The Rockefeller University Press.