DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death

doi:10.1083/jcb.200109094

Published 29 April 2002. doi:10.1083/jcb.200109094

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© The Rockefeller University Press, 0021-9525/2002/4/455 $5.00
The Journal of Cell Biology, Volume 157, Number 3, April 29, 2002 455-468

Article

DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death

Boaz Inbal¹, Shani Bialik¹, Ilana Sabanay², Gidi Shani¹ and Adi Kimchi¹

¹ Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
² Electron Microscopy Center, Weizmann Institute of Science, Rehovot 76100, Israel

Address correspondence to Adi Kimchi, Dept. of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-9342428. Fax: 972-8-9315938. E-mail: Adi.kimchi{at}weizmann.ac.il

Death-associated protein kinase (DAPk) and DAPk-related proteinkinase (DRP)-1 proteins are Ca⁺²/calmodulin–regulatedSer/Thr death kinases whose precise roles in programmed celldeath are still mostly unknown. In this study, we dissectedthe subcellular events in which these kinases are involved duringcell death. Expression of each of these DAPk subfamily membersin their activated forms triggered two major cytoplasmic events:membrane blebbing, characteristic of several types of cell death,and extensive autophagy, which is typical of autophagic (typeII) programmed cell death. These two different cellular outcomeswere totally independent of caspase activity. It was also foundthat dominant negative mutants of DAPk or DRP-1 reduced membraneblebbing during the p55/tumor necrosis factor receptor 1–inducedtype I apoptosis but did not prevent nuclear fragmentation.In addition, expression of the dominant negative mutant of DRP-1or of DAPk antisense mRNA reduced autophagy induced by antiestrogens,amino acid starvation, or administration of interferon- ${gamma}$ . Thus,both endogenous DAPk and DRP-1 possess rate-limiting functionsin these two distinct cytoplasmic events. Finally, immunogoldstaining showed that DRP-1 is localized inside the autophagicvesicles, suggesting a direct involvement of this kinase inthe process of autophagy.

Key Words: DAP kinase; DRP-1; autophagy; membrane blebbing; programmed cell death

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