Abstract
Gelsolin is a Ca2+-dependent actin-regulatory protein that modulates actin assembly and disassembly, and is believed to regulate cell motility through modulation of the actin network. Gelsolin was also recently suggested to be involved in the regulation of apoptosis: human gelsolin (hGsn) has anti-apoptotic activity, whereas mouse gelsolin (mGsn) exerts either proapoptotic or anti-apoptotic activity depending on different cell types. Here, we studied the basis of anti-apoptotic activity of hGsn. We showed that both endogenous and overexpressed hGsn has anti-apoptotic activity, that depends on its C-terminal half. We also found that hGsn and its C-terminal half but not mGsn could prevent apoptotic mitochondrial changes such as Δψ loss and cytochrome c release in isolated mitochondria to a similar extent as Bcl-xL, indicating that hGsn targets the mitochondria to prevent apoptosis via its C-terminal half. In the same way as anti-apoptotic Bcl-xL, which we recently found to prevent apoptotic mitochondrial changes by binding and closing the voltage-dependent anion channel (VDAC), hGsn and its C-terminal half inhibited the activity of VDAC on liposomes through direct binding in a Ca2+-dependent manner. These results suggest that hGsn inhibits apoptosis by blocking mitochondrial VDAC activity.
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Abbreviations
- VDAC:
-
voltage-dependent anion channel
- Gsn:
-
gelsolin
- GST:
-
glutatione S-transferase: Δψ, mitochondrial membrane potential
- AIF:
-
apoptosis-inducing factor
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Acknowledgements
We thank H Terada and Y Shinohara for providing anti-human VDAC polyclonal antibody. This study was supported in part by a grant for Scientific Research on Priority Areas, by a grant for Center of Excellence Research, by a grant for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and by Special Coordination Funds for Promoting Science and Technology from the Science and Technology Agency of Japan.
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Kusano, H., Shimizu, S., Koya, R. et al. Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC. Oncogene 19, 4807–4814 (2000). https://doi.org/10.1038/sj.onc.1203868
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DOI: https://doi.org/10.1038/sj.onc.1203868
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