Yang Y, Fang S, Jensen J P, Weissman A M, Ashwell J D
Laboratory of Immune Cell Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Science. 2000 May 5;288(5467):874-7. doi: 10.1126/science.288.5467.874.
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.
为了确定蛋白酶体抑制剂阻止胸腺细胞死亡的原因，我们研究了蛋白酶体是否会降解诱导凋亡细胞中的抗凋亡分子。在死亡前，凋亡的c-IAP1和XIAP抑制剂在糖皮质激素或依托泊苷处理的胸腺细胞中以蛋白酶体依赖的方式选择性丧失。IAPs在体外催化自身泛素化，该活性需要RING结构域。过表达的野生型c-IAP1，而不是RING结构域突变体，会自发泛素化并降解，并且缺乏RING结构域的稳定表达的XIAP对凋亡诱导的降解相对抗性，相应地，在预防凋亡方面比野生型XIAP更有效。IAPs的自泛素化和降解可能是凋亡程序中的关键事件。
