Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli
Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli
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DOI：
10.1126/science.288.5467.874
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发表时间：
2000-05-05
期刊：
影响因子：
56.9
通讯作者：
Ashwell, JD
中科院分区：
文献类型：
--
作者：
Yang, Y;Fang, SY;Ashwell, JD
为了确定蛋白酶体抑制剂为何能阻止胸腺细胞死亡，我们检测了在诱导发生凋亡的细胞中蛋白酶体是否降解抗凋亡分子。在死亡之前，糖皮质激素或依托泊苷处理的胸腺细胞中，凋亡抑制蛋白c - IAP1和XIAP以蛋白酶体依赖的方式选择性地缺失。IAPs在体外可催化自身泛素化，这种活性需要RING结构域。过表达的野生型c - IAP1（而非RING结构域突变体）会自发地发生泛素化和降解，而稳定表达的缺失RING结构域的XIAP对凋亡诱导的降解相对具有抗性，并且相应地，在阻止凋亡方面比野生型XIAP更有效。IAPs的自身泛素化和降解可能是凋亡程序中的一个关键事件。
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.