Ubiquitin Protein Ligase Activity of IAPs and Their Degradation in Proteasomes in Response to Apoptotic Stimuli

TLDR

Autoubiquitination and degradation of IAPs may be a key event in the apoptotic program. The study aimed to determine why proteasome inhibitors prevent thymocyte death by investigating whether proteasomes degrade anti‑apoptotic molecules in apoptosis‑induced thymocytes. Researchers examined proteasome‑mediated degradation of anti‑apoptotic molecules in thymocytes induced to undergo apoptosis. c‑IAP1 and XIAP are selectively degraded by proteasomes before thymocyte death, a process requiring their RING‑domain–mediated autoubiquitination; wild‑type c‑IAP1 is spontaneously ubiquitinated and degraded, whereas a RING mutant is not, and XIAP lacking the RING domain resists degradation and more effectively blocks apoptosis.

Abstract

To determine why proteasome inhibitors prevent thymocyte death, we examined whether proteasomes degrade anti-apoptotic molecules in cells induced to undergo apoptosis. The c-IAP1 and XIAP inhibitors of apoptosis were selectively 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-IAP1, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wild-type XIAP. Autoubiquitination and degradation of IAPs may be a key event in the apoptotic program.