BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells

NF-kappaB is usually activated by signal-induced, ubiquitin-mediated degradation of its inhibitor, IkappaB. This process is initiated by phosphorylation of IkappaB by the IkappaB kinase (IKK) complex, predominantly by the IKKbeta catalytic subunit, and requires the regulatory subunit IKKgamma (NEMO). Another activation pathway, with no known physiological inducers, involves ubiquitin-mediated processing of the NF-kappaB2 inhibitory protein p100 and is dependent on phosphorylation of p100 by IKKalpha. We show here that B cell-activating factor (BAFF) activates this second pathway and that this requires the BAFF receptor (BAFF-R), the NF-kappaB-inducing kinase (NIK) and protein synthesis, but not NEMO. This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells.