Mitochondrial shuttling of CAP1 promotes actin- and cofilin-dependent apoptosis.
Mitochondria play a central role in regulating apoptosis by releasing proapoptotic contents such as cytochrome c, and generating reactive oxygen species (ROS). Early in apoptosis, proteins translocate to mitochondria to promote the release of their contents. Here, we show that the actin- and cofilin-interacting protein CAP1 has a role in apoptosis. When we induced apoptosis, CAP1 rapidly translocated to the mitochondria independently of caspase activation. Translocation was proapoptotic because CAP1-knockdown cells were resistant to apoptosis inducers. Overexpression of wild-type CAP1 did not stimulate apoptosis on its own, but stimulated cofilin-induced apoptosis. Apoptosis induction required a mitochondrial-targeting domain, localized in the N-terminus and also the actin-binding domain in the C-terminus. Taken together, these studies suggest that CAP1 provides a direct link from the actin cytoskeleton to the mitochondria by functioning as an actin shuttle.
Wang
Changhui
C
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Zhou
Guo-Lei
GL
Vedantam
Srilakshmi
S
Li
Peng
P
Field
Jeffrey
J
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding; D021381:Protein Transport
D051339:Actin Depolymerizing Factors; D000199:Actins; C489549:CAP1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C525401:CAP1 cyclase-associated protein, mouse; D045304:Cytochromes c