BH3-only Activator Proteins Bid and Bim Are Dispensable for Bak/Bax-dependent Thrombocyte Apoptosis Induced by Bcl-xL Deficiency MOLECULAR REQUISITES FOR THE MITOCHONDRIAL PATHWAY TO APOPTOSIS IN PLATELETS
BH3-only Activator Proteins Bid and Bim Are Dispensable for Bak/Bax-dependent Thrombocyte Apoptosis Induced by Bcl-xL Deficiency MOLECULAR REQUISITES FOR THE MITOCHONDRIAL PATHWAY TO APOPTOSIS IN PLATELETS
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DOI：
10.1074/jbc.m110.195370
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发表时间：
2011-04-22
影响因子：
4.8
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
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作者：
Kodama, Takahiro;Takehara, Tetsuo;Hayashi, Norio
线粒体凋亡途径中的关键步骤是Bak和Bax的激活，尽管其分子机制仍有争议。为了验证线粒体的凋亡是否可以由缺乏抗凋亡的Bcl2样蛋白或需要BH3蛋白的直接激活剂(包括Bid和Bim)来诱导，我们研究了Bclxl缺乏诱导血小板凋亡的分子条件。在Bak和Bax双基因敲除背景下，血栓细胞特异性的BclxL基因敲除所致的严重血小板减少症被完全挽救，但没有一种基因敲除。与此形成鲜明对比的是，缺乏Bid、Bim或两者都不能缓解Bl-xl基因敲除小鼠的血小板减少症。体外研究表明，ABT-737是一种Bad模拟物，通过氨基末端构象改变、从胞浆到线粒体的移位以及Bax的同源寡聚，诱导了血小板的凋亡。在Bid/Bim缺陷的血小板中，也观察到ABT-737诱导的Bax活化和细胞凋亡。尽管Bid和Bim的表达减少，但储存后的人血小板经历了自发的凋亡，并逐渐下降了Bclxl的表达。保存时，Bak/Bax缺陷或Bclxl过表达的血小板的细胞凋亡率降低，而Bid/Bim缺陷的血小板则无明显变化。综上所述，血小板寿命受抗和促凋亡多结构域Bcl2家族蛋白之间的微妙平衡调节。尽管BH3-唯一的激活蛋白Bid和Bim存在于血小板中，但它们对Bax的激活和线粒体的凋亡都是必不可少的。
A pivotal step in the mitochondrial pathway of apoptosis is activation of Bak and Bax, although the molecular mechanism remains controversial. To examine whether mitochondrial apoptosis can be induced by just a lack of antiapoptotic Bcl-2-like proteins or requires direct activators of the BH3-only proteins including Bid and Bim, we studied the molecular requisites for platelet apoptosis induced by Bcl-xL deficiency. Severe thrombocytopenia induced by thrombocyte-specific Bcl-xL knock-out was fully rescued in a Bak and Bax double knock-out background but not with single knock-out of either one. In sharp contrast, deficiency of either Bid, Bim, or both did not alleviate thrombocytopenia in Bcl-xL knock-out mice. An in vitro study revealed that ABT-737, a Bad mimetic, induced platelet apoptosis in association with a conformational change of the amino terminus, translocation from the cytosol to mitochondria, and homo-oligomerization of Bax. ABT-737-induced Bax activation and apoptosis were also observed in Bid/Bim-deficient platelets. Human platelets, upon storage, underwent spontaneous apoptosis with a gradual decline of Bcl-xL expression despite a decrease in Bid and Bim expression. Apoptosis was attenuated in Bak/Bax-deficient or Bcl-xL-overexpressing platelets but not in Bid/Bim-deficient platelets upon storage. In conclusion, platelet lifespan is regulated by a fine balance between anti-and proapoptotic multidomain Bcl-2 family proteins. Despite residing in platelets, BH3-only activator proteins Bid and Bim are dispensable for Bax activation and mitochondrial apoptosis.