Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria.
Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria.
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DOI：
10.1073/pnas.2021175118
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发表时间：
2021-08-17
影响因子：
11.1
通讯作者：
Edlich F
中科院分区：
文献类型：
--
作者：
Lauterwasser J;Fimm-Todt F;Oelgeklaus A;Schreiner A;Funk K;Falquez-Medina H;Klesse R;Jahreis G;Zerbes RM;O'Neill K;van der Laan M;Luo X;Edlich F
细胞表面的受体-配体相互作用或内在应激信号可以使哺乳动物细胞凋亡。在这项研究中，我们发现己糖激酶如何通过特异性抑制B细胞淋巴瘤2（BCL-2）蛋白来抵抗受体介导的细胞凋亡。己糖激酶将激活剂和效应物BCL-2蛋白从线粒体逆转运到胞质溶胶中。己糖激酶依赖的BCL-2蛋白逆转录可以保护细胞免于凋亡，尽管死亡受体信号传导。在许多哺乳动物细胞中，死亡受体介导的凋亡需要线粒体凋亡途径。响应于死亡受体信号传导，截短的仅BH 3蛋白BID可以激活促凋亡BCL-2蛋白BAX和巴克并触发线粒体的透化。促生存BCL-2蛋白通过从线粒体到胞质溶胶的逆转位抑制BAX和巴克，但对截短的BID依赖性细胞凋亡的特定抗性机制尚不清楚。在这里，我们报告说，己糖激酶1和己糖激酶2抑制凋亡激活剂截短BID以及效应BAX和巴克从线粒体到胞质溶胶的retrotranslocation。BCL-2蛋白穿梭和保护免于TRAIL和FasL诱导的细胞死亡需要线粒体己糖激酶定位和与BCL-2蛋白的BH 3基序的相互作用，但不需要葡萄糖磷酸化。总之，我们的工作建立了己糖激酶依赖性逆转录截短BID作为一种选择性保护机制，对死亡受体诱导的线粒体凋亡。
Receptor–ligand interactions on the cell surface or intrinsic stress signals can commit mammalian cells to apoptosis. In this study, we discover how hexokinases confer resistance to receptor-mediated apoptosis through specific inhibition of B-cell lymphoma 2 (BCL-2) proteins. Hexokinases retrotranslocate activator and effector BCL-2 proteins from the mitochondria into the cytosol. Hexokinase-dependent BCL-2 protein retrotranslocation can protect cells from apoptosis despite death receptor signaling. Death receptor–mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor–induced apoptosis on the mitochondria.
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影响因子：
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作者：
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通讯作者：
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