Nature Cell Biology5, 1083 - 1089 (2003)
Published online: 23 November 2003; | doi:10.1038/ncb1070
Mitochondrial translocation of cofilin is an early step in apoptosis induction
Boon Tin Chua1, Christiane Volbracht1, Kuan Onn Tan2, Rong Li3, Victor C. Yu2, 4
& Peng Li1, 5
1
Laboratories of Apoptosis Regulation, National Institute of Singapore, 30 Medical Drive, 117609, Singapore.
2
Mechanisms of Apoptosis in Mammalian Cells, National Institute of Singapore, 30 Medical Drive, 117609, Singapore.
3
Proteomics, Institute of Molecular and Cell Biology, National Institute of Singapore, 30 Medical Drive, 117609, Singapore.
4
Adjunct staff of the Department of Pharmacology, National University of Singapore, 18 Medical Drive, Singapore, 119260.
5
Department of Biology, Hong Kong University of Science and Technology, Clear water bay, Kowloon, Hong Kong.
Correspondence should be addressed to Peng Li bolipeng@ust.hk
Increasing evidence suggests that movement of key proteins in or out of mitochondria during apoptosis is essential for the regulation of apoptosis. Here, we report identification of the actin-binding protein cofilin by a proteomic approach, as such a factor translocated from cytosol into mitochondria after induction of apoptosis. We found that after induction of apoptosis, cofilin was translocated to mitochondria before release of cytochrome c. Reduction of cofilin protein levels with small-interfering RNA (siRNA) resulted in inhibition of both cytochrome c release and apoptosis. Only dephosphorylated cofilin was translocated to mitochondria, and the cofilin S3D mutant, which mimicks the phosphorylated form, suppressed mitochondrial translocation and apoptosis. Translocation was achieved through exposure of an amino-terminal mitochondrial targeting signal in combination with carboxy-terminal sequences. When correctly targeted to mitochondria, cofilin induced massive apoptosis. The apoptosis-inducing ability of cofilin, but not its mitochondrial localization, was dependent on the functional actin-binding domain. Thus, domains involved in mitochondrial targeting and actin binding are indispensable for its pro-apoptotic function. Our data suggest that cofilin has an important function during the initiation phase of apoptosis.
