The intrinsic apoptosis pathway, regulated by the BCL-2 protein family, is essential for embryonic development. Using mice lacking all known apoptosis effectors, BAX, BAK and BOK, we have previously defined the processes during development that require apoptosis. Rare Bok^−/−Bax^−/−Bak^−/− triple knockout (TKO) mice developed to adulthood and several tissues that were thought to require apoptosis during development appeared normal. This raises the question if all apoptosis had been abolished in the TKO mice or if other BCL-2 family members could act as effectors of apoptosis. Here, we investigated the role of BID, generally considered to link the extrinsic and intrinsic apoptosis pathways, acting as a BH3-only protein initiating apoptosis upstream of BAX and BAK. We found that Bok^−/−Bax^−/− Bak^−/−Bid^−/− quadruple knockout (QKO) mice have additional developmental anomalies compared to TKO mice, consistent with a role of BID, not only upstream but also in parallel to BAX, BAK and BOK. Mitochondrial experiments identified a small cytochrome c-releasing activity of full-length BID. Collectively, these findings suggest a new effector role for BID in the intrinsic apoptosis pathway.

中文翻译：

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BCL-2 家族成员 BID 除了仅具有 BH3 蛋白功能外，还通过与 BAX、BAK 和 BOK 并行作用，在胚胎发育过程中发挥作用


由 BCL-2 蛋白家族调节的内在凋亡途径对于胚胎发育至关重要。使用缺乏所有已知细胞凋亡效应子 BAX、BAK 和 BOK 的小鼠，我们之前已经定义了发育过程中需要细胞凋亡的过程。罕见的 Bok ^−/− Bax ^−/− Bak ^−/−三重敲除 (TKO) 小鼠发育至成年，并且一些被认为在发育过程中需要细胞凋亡的组织看起来正常。这就提出了一个问题：TKO 小鼠中是否所有细胞凋亡都已被消除，或者其他 BCL-2 家族成员是否可以充当细胞凋亡的效应器。在这里，我们研究了 BID 的作用，通常被认为连接外在和内在细胞凋亡途径，作为 BH3-only 蛋白启动 BAX 和 BAK 上游的细胞凋亡。我们发现，与 TKO 小鼠相比，Bok ^−/− Bax ^−/− Bak ^−/− Bid ^−/−四重基因敲除 (QKO) 小鼠具有额外的发育异常，这与 BID 的作用一致，不仅在上游，而且与 BAX 平行、比克和博克。线粒体实验鉴定出全长 BID 的小细胞色素 c 释放活性。总的来说，这些发现表明 BID 在内在凋亡途径中具有新的效应器作用。