A switch in distinct IκBα degradation mechanisms mediates constitutive NF-κB activation in mature B cells

Inducible activation of cytoplasmic NF-κB/Rel transcription factors occurs via proteasome-dependent degradation of an associated inhibitor, termed IκBa. Mature B lymphocytes constitutively express nuclear NF-κB, which is important for their long-term survival. The intrinsic mechanisms by which B cells constitutively activate NF-κB are unknown. In this paper we demonstrate that maintenance of NF-κB activity in primary B cells is mediated by a novel calcium-dependent, but proteasome-independent, mechanism. Moreover, we show that differentiation of conditionally transformed pre-B cells is accompanied by a switch from proteasome-dependent to proteasome- independent degradation of IκBα. Our findings indicate that IκBα degradation mechanisms are dynamic during B cell development, and ultimately establish constitutive NF-κB activity in mature B lymphocytes.