Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Cell Death Differ. 2023 Mar;30(3):753-765. doi: 10.1038/s41418-022-01080-2. Epub 2022 Nov 3.
The anti-apoptotic MCL1 is critical for delaying apoptosis during mitotic arrest. MCL1 is degraded progressively during mitotic arrest, removing its anti-apoptotic function. We found that knockout of components of ubiquitin ligases including APC/C, SCF complexes, and the mitochondrial ubiquitin ligase MARCH5 did not prevent mitotic degradation of MCL1. Nevertheless, MARCH5 determined the initial level of MCL1-NOXA network upon mitotic entry and hence the window of time during MCL1 was present during mitotic arrest. Paradoxically, although knockout of MARCH5 elevated mitotic MCL1, mitotic apoptosis was in fact enhanced in a BAK-dependent manner. Mitotic apoptosis was accelerated after MARCH5 was ablated in both the presence and absence of MCL1. Cell death was not altered after disrupting other MARCH5-regulated BCL2 family members including NOXA, BIM, and BID. Disruption of the mitochondrial fission factor DRP1, however, reduced mitotic apoptosis in MARCH5-disrupted cells. These data suggest that MARCH5 regulates mitotic apoptosis through MCL1-independent mechanisms including mitochondrial maintenance that can overcome the stabilization of MCL1.
抗凋亡蛋白 MCL1 对于有丝分裂阻滞期间的凋亡延迟至关重要。MCL1 在有丝分裂阻滞期间逐渐降解，从而去除其抗凋亡功能。我们发现，敲除泛素连接酶 APC/C、SCF 复合物和线粒体泛素连接酶 MARCH5 的组件并不能阻止 MCL1 的有丝分裂降解。然而，MARCH5 决定了有丝分裂进入时 MCL1-NOXA 网络的初始水平，因此在有丝分裂阻滞期间存在 MCL1 的时间窗口。矛盾的是，尽管敲除 MARCH5 会增加有丝分裂 MCL1，但实际上有丝分裂凋亡是以 BAK 依赖性方式增强的。在存在和不存在 MCL1 的情况下，MARCH5 被剔除后，有丝分裂凋亡会加速。破坏包括 NOXA、BIM 和 BID 在内的其他 MARCH5 调节的 BCL2 家族成员后，细胞死亡没有改变。然而，破坏线粒体裂变因子 DRP1 会减少 MARCH5 破坏细胞中的有丝分裂凋亡。这些数据表明，MARCH5 通过独立于 MCL1 的机制（包括线粒体维持）来调节有丝分裂凋亡，这些机制可以克服 MCL1 的稳定。
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