A UNIFIED PATHWAY FOR THE DEGRADATION OF ORNITHINE DECARBOXYLASE IN RETICULOCYTE LYSATE REQUIRES INTERACTION WITH THE POLYAMINE-INDUCED PROTEIN, ORNITHINE DECARBOXYLASE ANTIZYME

Recent studies have provided convincing evidence to add to a number of earlier observations suggesting that the rapid intracellular degradat ion of mammalian ornithine decarboxylase (ODC) is further accelerated by the action of ornithine decarboxylase antizyme (ODC-Az), a polyamin e-induced protein. However, the mechanism whereby ODC-Az exerts its ef fect in this proteolytic process is mostly unknown. Here, by using ret iculocyte-lysate-based synthesis and degradation systems, we demonstra te that interaction of ODC-Az with ODC results in two related outcomes : (a) ODC is inactivated as a result of its monomerization, and (b) OD C degradation is dramatically accelerated. While ODC inactivation requ ires the integrity of the ODC-Az binding site of ODC and the ODC bindi ng site of ODC-Az, acceleration in ODC degradation also requires the p reviously characterized carboxyl-terminal destabilizing segment of ODC and a specific segment of ODC-Az that may be functionally distinct fr om that required for ODC binding. Interestingly, an active ODC variant with a mutant ODC-Az binding site is stable under basal degradation c onditions. This, together with the ability of anti-(ODC-Az) antibody t o specifically inhibit the basal degradation of ODC in the lysate, sug gests that ODC-Az is an essential general mediator of ODC degradation. Based on these observations, we propose a model for the degradation o f ODC which always require interaction with antizyme.