Wilson Rebecca, Goyal Lakshmi, Ditzel Mark, Zachariou Anna, Baker David A, Agapite Julie, Steller Hermann, Meier Pascal
The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
Nat Cell Biol. 2002 Jun;4(6):445-50. doi: 10.1038/ncb799.
Members of the Inhibitor of Apoptosis Protein (IAP) family block activation of the intrinsic cell death machinery by binding to and neutralizing the activity of pro-apoptotic caspases. In Drosophila melanogaster, the pro-apoptotic proteins Reaper (Rpr), Grim and Hid (head involution defective) all induce cell death by antagonizing the anti-apoptotic activity of Drosophila IAP1 (DIAP1), thereby liberating caspases. Here, we show that in vivo, the RING finger of DIAP1 is essential for the regulation of apoptosis induced by Rpr, Hid and Dronc. Furthermore, we show that the RING finger of DIAP1 promotes the ubiquitination of both itself and of Dronc. Disruption of the DIAP1 RING finger does not inhibit its binding to Rpr, Hid or Dronc, but completely abrogates ubiquitination of Dronc. Our data suggest that IAPs suppress apoptosis by binding to and targeting caspases for ubiquitination.
凋亡抑制蛋白（IAP）家族成员通过结合并中和促凋亡半胱天冬酶的活性来阻断内在细胞死亡机制的激活。在黑腹果蝇中，促凋亡蛋白收割者（Rpr）、严峻蛋白（Grim）和头部内卷缺陷蛋白（Hid）均通过拮抗果蝇IAP1（DIAP1）的抗凋亡活性来诱导细胞死亡，从而释放半胱天冬酶。在此，我们表明在体内，DIAP1的环状结构域对于调控由Rpr、Hid和Dronc诱导的凋亡至关重要。此外，我们还表明DIAP1的环状结构域促进其自身以及Dronc的泛素化。DIAP1环状结构域的破坏并不抑制其与Rpr、Hid或Dronc的结合，但完全消除了Dronc的泛素化。我们的数据表明，IAP通过结合并靶向半胱天冬酶进行泛素化来抑制凋亡。
