A primary step in activating the alternative nuclear factor-kappaB (NF-kappaB) 
pathway requires NF-kappaB2/p100 processing to generate p52. In most cases, 
stimuli-induced p100 processing is dependent on NF-kappaB-inducing 
kinase/IkappaB kinase alpha-mediated phosphorylation and ubiquitination. Here, 
we report that post-translational modification of p100 at specific sites by the 
small ubiquitin-like modifier (SUMO) is another determining factor for 
stimuli-induced p100 processing. The results show that basal SUMO modification 
is required for stimuli-induced p100 phosphorylation and that blocking 
SUMOylation of p100, either by site-directed mutation or by short interfering 
RNA-targeted diminution of E2 SUMO-conjugating enzyme Ubc9, inhibits various 
physiological stimuli-induced p100 processing and ultimate activation of the 
alternative NF-kappaB pathway. Together, these findings show the crucial role of 
SUMO1 modification in p100 processing and provide mechanistic insights into the 
participation of SUMO1 modification in the regulation of signal transduction.