Dysregulation of a potassium channel, THIK-1, targeted by caspase-8 accelerates cell shrinkage
| Autor: | Takeharu Nagai, Haruyo Sugimoto, Akira Nozawa, Kiwamu Takemoto, Yutaka Satou, Naoto Ueno, Tatsuya Sawasaki, Sang-Kee Jung, Kumiko Chiba, Hirotaka Takahashi, Ayako Takeuchi, Satoshi Matsuoka, Takahiro Ishii, Kazuhiro Sakamaki, Koji Koyamada, Ryo Morishita, Akiko Saito, Shuhei Tamate, Toshiya Sakata, Chiyo Takagi, Hajime Shinoda |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Time Factors Cell Xenopus Apoptosis Transfection Caspase 8 Substrate Specificity Xenopus laevis 03 medical and health sciences Potassium Channels Tandem Pore Domain RNA interference Chlorocebus aethiops medicine Animals Humans Protein Interaction Domains and Motifs Molecular Biology Caspase Cell Size biology Cell Biology biology.organism_classification Potassium channel Cell biology Enzyme Activation 030104 developmental biology medicine.anatomical_structure COS Cells Mutation MCF-7 Cells biology.protein RNA Interference Intracellular HeLa Cells Protein Binding Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1863:2766-2783 |
| ISSN: | 0167-4889 |
| DOI: | 10.1016/j.bbamcr.2016.08.010 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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