The human Bcl-2 family member Bcl-rambo and voltage-dependent anion channels manifest a genetic interaction in Drosophila and cooperatively promote the activation of effector caspases in human cultured cells
The human Bcl-2 family member Bcl-rambo and voltage-dependent anion channels manifest a genetic interaction in Drosophila and cooperatively promote the activation of effector caspases in human cultured cells
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DOI：
10.1016/j.yexcr.2019.05.015
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发表时间：
2019-08-15
影响因子：
3.7
通讯作者：
Kataoka, Takao
中科院分区：
文献类型：
--
作者：
Matsubara, Hisanori;Tanaka, Reiji;Kataoka, Takao
我们先前报道了Bcl-2家族成员人Bcl-rambo，也称为BCL 2L 13，诱导人胚肾293 T细胞凋亡。最近有报道小鼠Bcl-rambo介导线粒体断裂和线粒体自噬。在本研究中，我们发现，转染人Bcl-rambo及其微管相关蛋白轻链3-相互作用区基序突变体（W276 A/I279 A）引起人肺腺癌A549细胞中的线粒体片段化和片段化线粒体的核周积累。在使用果蝇模型的综合筛选中，其中人类Bcl-rambo异位表达于眼成虫盘中，发现电压依赖性阴离子通道（VDAC），也称为线粒体孔蛋白，表现出与人类Bcl-rambo的遗传相互作用。除了人腺嘌呤核苷酸移位酶（ANT）1和ANT 2之外，人Bcl-rambo蛋白结合人VDAC 1，尽管结合程度低于ANT 2。此外，人VDAC 1和人VDAC 2仅在293 T细胞中与人Bcl-rambo共表达时才特别促进效应子半胱天冬酶的活化。Bcl-rambo通过敲低A549细胞中的VDAC 1、VDAC 2和VDAC 3诱导破碎的线粒体在核周积聚。因此，本研究揭示了人Bcl-rambo和VDAC协同促进人培养细胞中效应器半胱天冬酶的活化。
We previously reported that the Bcl-2 family member human Bcl-rambo, also known as BCL2L13, induces apoptosis in human embryonic kidney 293T cells. Mouse Bcl-rambo has recently been reported to mediate mitochondrial fragmentation and mitophagy. In the present study, we showed that the transfection of human Bcl-rambo and its microtubule-associated protein light chain 3-interacting region motif mutant (W276A/I279A) caused mitochondrial fragmentation and the perinuclear accumulation of fragmented mitochondria in human lung adenocarcinoma A549 cells. In comprehensive screening using the Drosophila model in which human Bcl-rambo was ectopically expressed in eye imaginal discs, voltage-dependent anion channels (VDAC), also known as mitochondrial porin, were found to manifest a genetic interaction with human Bcl-rambo. In addition to human adenine nucleotide translocase (ANT) 1 and ANT2, the human Bcl-rambo protein bound to human VDAC1, albeit to a lesser extent than ANT2. Moreover, human VDAC1 and human VDAC2 in particular promoted the activation of effector caspases only when they were co-expressed with human Bcl-rambo in 293T cells. Bcl-rambo induced the perinuclear accumulation of fragmented mitochondria by the knockdown of VDAC1, VDAC2, and VDAC3 in A549 cells. Thus, the present study revealed that human Bcl-rambo and VDAC cooperatively promote the activation of effector caspases in human cultured cells.