Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli

To determine why proteasome inhibitors prevent thymocyte death, we examined whether proteasomes degrade anti-apoptotic molecules in cells induced to u ndergo apoptosis, The c-IAP1 and XIAP inhibitors of apoptosis were selectiv ely lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome -dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wild-type c-IAP 1, but not a RING domain mutant, was spontaneously ubiquitinated and degrad ed, and stably expressed XIAP lacking the RING domain was relatively resist ant to apoptosis-induced degradation and, correspondingly, more effective a t preventing apoptosis than wild-type XIAP. Autoubiquitination and degradat ion of IAPs may be a key event in the apoptotic program.