Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak.
Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak.
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DOI：
10.7554/elife.30543
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发表时间：
2017-11-17
期刊：
影响因子：
7.7
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Karch J;Schips TG;Maliken BD;Brody MJ;Sargent MA;Kanisicak O;Molkentin JD
已知在促死亡基因Bcl2家族成员Bax和Bak中缺失的细胞对凋亡细胞死亡具有抵抗力，此前我们已经证明，这两个效应器也是线粒体依赖性细胞坏死所必需的(Kch等人，2013年)。在这里，我们证明了Bax/Bak1缺陷的小鼠胚胎成纤维细胞通过涉及溶酶体通透性的机制来抵抗与自噬相关的第三种主要形式的细胞死亡。事实上，仅针对溶酶体靶向Bax可以恢复Bax/Bak1缺失细胞中的自噬细胞死亡。此外，Bax的单体突变形式足以增加Bax/Bak1双缺失小鼠胚胎成纤维细胞的溶酶体膜通透性和恢复自噬细胞死亡。最后，在缺乏Bax/Bak1的细胞中，通过溶体亲和性洗涤剂增加溶酶体的通透性可以恢复自噬细胞死亡，共同表明Bax/Bak通过直接影响细胞内多个细胞器的膜通透性整合了所有主要形式的细胞死亡。
Cells deficient in the pro-death Bcl-2 family members Bax and Bak are known to be resistant to apoptotic cell death, and previous we have shown that these two effectors are also needed for mitochondrial-dependent cellular necrosis (Karch et al., 2013). Here we show that mouse embryonic fibroblasts deficient in Bax/Bak1 are resistant to the third major form of cell death associated with autophagy through a mechanism involving lysosome permeability. Indeed, specifically targeting Bax only to the lysosome restores autophagic cell death in Bax/Bak1 null cells. Moreover, a monomeric-only mutant form of Bax is sufficient to increase lysosomal membrane permeability and restore autophagic cell death in Bax/Bak1 double-deleted mouse embryonic fibroblasts. Finally, increasing lysosomal permeability through a lysomotropic detergent in cells devoid of Bax/Bak1 restores autophagic cell death, collectively indicting that Bax/Bak integrate all major forms of cell death through direct effects on membrane permeability of multiple intracellular organelles.