Genetic evidence for the essential role of β-transducin repeat-containing protein in the inducible processing of NF-κB2/p100

Abstract

Processing of the nfκb2 gene product p100 to generate p52 is an important step in NF-κB regulation. This step is regulated by a nonclassical NF-κB signaling pathway involving the NF-κB-inducing kinase (NIK). NIK induces p100 processing by triggering phosphorylation of specific C-terminal serines of p100. However, the downstream molecular events leading to p100 processing remain unclear. Here we show that NIK induced the physical recruitment of β-transducin repeat-containing protein (β-TrCP), a component of the SCF ubiquitin ligase complex, to p100. This event required the phosphorylation sites as well as the death domain of p100. Using the RNA interference technique, we demonstrated that β-TrCP is essential for NIK-induced p100 ubiquitination and processing. Interestingly the constitutive processing of p100 mutants was independent of β-TrCP. These results suggest that β-TrCP is an essential component of NIK-induced p100 processing.