Cells deficient in the pro-death Bcl-2 family members Bax and Bak are known to be resistant to apoptotic cell death, and in a previous eLIFE paper, Karch et al., 2013 showed that these 2 effectors are also needed for mitochondrial-dependent cellular necrosis. 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.

已知死亡前Bcl-2家族成员Bax和Bak的细胞对凋亡性细胞死亡具有抗性，在先前的eLIFE论文中，Karch等人，2013年表明线粒体依赖性还需要这两种效应子细胞坏死。在这里，我们显示缺乏Bax / Bak1的小鼠胚胎成纤维细胞通过涉及溶酶体通透性的机制，对与自噬相关的细胞死亡的第三种主要形式具有抗性。实际上，仅将Bax专门靶向溶酶体可恢复Bax / Bak1空细胞中的自噬细胞死亡。此外，Bax的仅单体突变体形式足以增加溶酶体膜通透性并恢复Bax / Bak1中的自噬细胞死亡。双删除的小鼠胚胎成纤维细胞。最后，在没有Bax / Bak1的细胞中通过溶溶性去污剂增加溶酶体通透性可恢复自噬细胞死亡，共同表明Bax / Bak通过直接作用于多个细胞内细胞器的膜通透性而整合了所有主要的细胞死亡形式。