Dysregulation of a potassium channel, THIK-1, targeted by caspase-8 accelerates cell shrinkage
Dysregulation of a potassium channel, THIK-1, targeted by caspase-8 accelerates cell shrinkage
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DOI：
10.1016/j.bbamcr.2016.08.010
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发表时间：
2016-11-01
影响因子：
5.1
通讯作者：
Ueno, Naoto
中科院分区：
文献类型：
--
作者：
Sakamaki, Kazuhiro;Ishii, Takahiro M.;Ueno, Naoto
半胱天冬酶的激活对于细胞凋亡的执行至关重要。尽管与起始半胱天冬酶 - 8（CASP8）激活相关的半胱天冬酶级联已在分子和生化细节方面得到了研究，但CASP8的生理作用尚未完全被理解。在此，我们鉴定出一种双孔结构域钾通道，即串联孔结构域氟烷抑制性K⁺通道1（THIK - 1），作为一种新的CASP8底物。在凋亡细胞中，THIK - 1的细胞内区域被CASP8切割。THIK - 1的过表达（而非其细胞内部分缺失CASP8靶向序列的突变体）会加速细胞在应对凋亡刺激时的收缩。相反，通过RNA干扰敲低内源性THIK - 1会导致收缩延迟和钾离子外流延迟。此外，一种缺失细胞内区域的截短的THIK - 1突变体（其模拟被CASP8切割后的形式）会导致培养细胞在无凋亡刺激的情况下细胞体积减小，并过度促进非洲爪蟾胚胎的不规则发育。综上所述，这些结果表明THIK - 1参与了细胞收缩的加速。因此，我们已经证明了CASP8的一种新的生理作用：创建一个级联反应，使细胞在凋亡过程中进入下一阶段。（C）2016爱思唯尔公司。保留所有权利。
Activation of caspases is crucial for the execution of apoptosis. Although the caspase cascade associated with activation of the initiator caspase-8 (CASP8) has been investigated in molecular and biochemical detail, the physiological role of CASP8 is not fully understood. Here, we identified a two-pore domain potassium channel, tandem-pore domain halothane-inhibited K+ channel 1 (THIK-1), as a novel CASP8 substrate. The intracellular region of THIK-1 was cleaved by CASP8 in apoptotic cells. Overexpression of THIK-1, but not its mutant lacking the CASP8-target sequence in the intracellular portion, accelerated cell shrinkage in response to apoptotic stimuli. In contrast, knockdown of endogenous THIK-1 by RNA interference resulted in delayed shrinkage and potassium efflux. Furthermore, a truncated THIK-1 mutant lacking the intracellular region, which mimics the form cleaved by CASP8, led to a decrease of cell volume of cultured cells without apoptotic stimulation and excessively promoted irregular development of Xenopus embryos. Taken together, these results indicate that THIK-1 is involved in the acceleration of cell shrinkage. Thus, we have demonstrated a novel physiological role of CASP8: creating a cascade that advances the cell to the next stage in the apoptotic process. (C) 2016 Elsevier B.V. All rights reserved.