Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Ohio, United States.
Howard Hughes Medical Institute, Cincinnati, United States.
Elife. 2017 Nov 17;6:e30543. doi: 10.7554/eLife.30543.
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 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 null cells. Moreover, a monomeric-only mutant form of Bax is sufficient to increase lysosomal membrane permeability and restore autophagic cell death in double-deleted mouse embryonic fibroblasts. Finally, increasing lysosomal permeability through a lysomotropic detergent in cells devoid of 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.
已知缺乏促死亡 Bcl-2 家族成员 Bax 和 Bak 的细胞对凋亡性细胞死亡具有抗性，并且我们之前已经表明这两种效应物对于线粒体依赖性细胞坏死也是必需的（Karch 等人，2013 年）。在这里，我们表明缺乏 的小鼠胚胎成纤维细胞对与自噬相关的第三种主要细胞死亡形式具有抗性，其机制涉及溶酶体通透性。事实上，仅将 Bax 特异性靶向溶酶体即可恢复 Bax 缺失细胞中的自噬性细胞死亡。此外， Bax 的单体仅突变形式足以增加溶酶体膜通透性并恢复 Bax/Bak 双缺失的小鼠胚胎成纤维细胞中的自噬性细胞死亡。最后，通过缺乏 Bax/Bak 的细胞中的溶酶体促进性去污剂增加溶酶体通透性可恢复自噬性细胞死亡，这些结果共同表明 Bax/Bak 通过直接影响多种细胞内细胞器的膜通透性来整合所有主要的细胞死亡形式。
