Sakamaki, K., Ishii, T.M., Sakata, T., Takemoto, K., Takagi, C., Takeuchi, A., Morishita, R., Takahashi, H., Nozawa, A., Shinoda, H., Chiba, K., Sugimoto, H., Saito, A., Tamate, S., Satou, Y., Jung, S.-K., Matsuoka, S., Koyamada, K., Sawasaki, T., Nagai, T., Ueno, N.
Biochimica et Biophysica Acta - Molecular Cell Research 1863 11 2766 - 2783 2016年
[査読有り][通常論文] 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.