Processing of the NF-kappaB2 precursor protein p100 to generate p52 is an 
important step of NF-kappaB regulation. This proteolytic event is tightly 
regulated by sequences located at the C-terminal portion of p100. Constitutive 
processing of p100 occurs in certain lymphoma cells due to the loss of its 
C-terminal regulatory domain, although the underlying mechanisms remain unknown. 
We show here that the constitutive processing of C-terminal truncation mutants 
of p100 is associated with their active nuclear translocation. Deletion of the 
C-terminal death domain of p100 triggers a low, but significant, level of 
nuclear translocation and processing. Disruption of the ankyrin-repeat domain of 
p100 further enhances its nuclear shuttling activity, which is again associated 
with elevated level of processing. More importantly, mutation of the nuclear 
localization signal (NLS) of p100 abolishes its processing, and this defect can 
be rescued by fusion of a heterologous NLS to the amino- or carboxyl-terminus of 
the p100 mutant. These results suggest that nuclear shuttling is a mechanism 
regulating the processing of NF-kappaB2/p100.