BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins
Release of apoptogenic proteins such as cytochrome c from mitochondria is regulated by pro- and anti-apoptotic Bcl-2 family proteins, with pro-apoptotic BH3-only proteins activating Bax and Bak. Current models assume that apoptosis induction occurs via the binding and inactivation of anti-apoptotic...
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| Veröffentlicht in: | The Journal of cell biology 2007-05, Vol.177 (4), p.625-636 |
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| container_title | The Journal of cell biology |
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| creator | Weber, Arnim Paschen, Stefan A Heger, Klaus Wilfling, Florian Frankenberg, Tobias Bauerschmitt, Heike Seiffert, Barbara M Kirschnek, Susanne Wagner, Hermann Häcker, Georg |
| description | Release of apoptogenic proteins such as cytochrome c from mitochondria is regulated by pro- and anti-apoptotic Bcl-2 family proteins, with pro-apoptotic BH3-only proteins activating Bax and Bak. Current models assume that apoptosis induction occurs via the binding and inactivation of anti-apoptotic Bcl-2 proteins by BH3-only proteins or by direct binding to Bax. Here, we analyze apoptosis induction by the BH3-only protein Bim(S). Regulated expression of Bim(S) in epithelial cells was followed by its rapid mitochondrial translocation and mitochondrial membrane insertion in the absence of detectable binding to anti-apoptotic Bcl-2 proteins. This caused mitochondrial recruitment and activation of Bax and apoptosis. Mutational analysis of Bim(S) showed that mitochondrial targeting, but not binding to Bcl-2 or Mcl-1, was required for apoptosis induction. In yeast, Bim(S) enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins. Thus, cell death induction by a BH3-only protein can occur through a process that is independent of anti-apoptotic Bcl-2 proteins but requires mitochondrial targeting. |
| doi_str_mv | 10.1083/jcb.200610148 |
| format | Article |
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Current models assume that apoptosis induction occurs via the binding and inactivation of anti-apoptotic Bcl-2 proteins by BH3-only proteins or by direct binding to Bax. Here, we analyze apoptosis induction by the BH3-only protein Bim(S). Regulated expression of Bim(S) in epithelial cells was followed by its rapid mitochondrial translocation and mitochondrial membrane insertion in the absence of detectable binding to anti-apoptotic Bcl-2 proteins. This caused mitochondrial recruitment and activation of Bax and apoptosis. Mutational analysis of Bim(S) showed that mitochondrial targeting, but not binding to Bcl-2 or Mcl-1, was required for apoptosis induction. In yeast, Bim(S) enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins. 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Current models assume that apoptosis induction occurs via the binding and inactivation of anti-apoptotic Bcl-2 proteins by BH3-only proteins or by direct binding to Bax. Here, we analyze apoptosis induction by the BH3-only protein Bim(S). Regulated expression of Bim(S) in epithelial cells was followed by its rapid mitochondrial translocation and mitochondrial membrane insertion in the absence of detectable binding to anti-apoptotic Bcl-2 proteins. This caused mitochondrial recruitment and activation of Bax and apoptosis. Mutational analysis of Bim(S) showed that mitochondrial targeting, but not binding to Bcl-2 or Mcl-1, was required for apoptosis induction. In yeast, Bim(S) enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins. Thus, cell death induction by a BH3-only protein can occur through a process that is independent of anti-apoptotic Bcl-2 proteins but requires mitochondrial targeting.</description><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Apoptosis Regulatory Proteins - biosynthesis</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Apoptosis Regulatory Proteins - physiology</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>Bcl-2-Like Protein 11</subject><subject>Cytosol - metabolism</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Membrane Proteins - biosynthesis</subject><subject>Membrane Proteins - metabolism</subject><subject>Membrane Proteins - physiology</subject><subject>Mice</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial Membranes - metabolism</subject><subject>Protein Binding</subject><subject>Protein Transport</subject><subject>Proto-Oncogene Proteins - biosynthesis</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins - physiology</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - physiology</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1v1DAQxS1ERZeFI1fkEzeX8VecXJBoxZdUqYfC2XIcLztVYmdtBwR_PSm7KvQ00sybN6P3I-QVhwsOrXx75_sLAdBw4Kp9QjZcK2AtV_CUbAAEZ50W-pw8L-UOAJRR8hk550Zz0zV8Qw6XON0yjMPiw0DdnOaaChaaw2HBHAqdsCa_T3HI6EY6Ju9G_O0qpkj7pdKYKsVYQ3b-b-8n1j11sSI7elX09NKPTNA5pxowlhfkbOfGEl6e6pZ8-_jh69Vndn3z6cvV-2vmJUDLuIGmHzqtZdfzthNdCCpoJ0WvudCqaaWQAcwgukaBNkbL-zXud32_M93g5Ja8O_rOSz-FwYdYsxvtnHFy-ZdNDu3jScS9_Z5-WAGNEmu0W_LmZJDTYQml2gmLD-PoYkhLsQb0GnorViE7Cn1OpeSwezjCwd5Dsisk-wBp1b_-_7N_6hMV-QdwJ49t</recordid><startdate>20070521</startdate><enddate>20070521</enddate><creator>Weber, Arnim</creator><creator>Paschen, Stefan A</creator><creator>Heger, Klaus</creator><creator>Wilfling, Florian</creator><creator>Frankenberg, Tobias</creator><creator>Bauerschmitt, Heike</creator><creator>Seiffert, Barbara M</creator><creator>Kirschnek, Susanne</creator><creator>Wagner, Hermann</creator><creator>Häcker, Georg</creator><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20070521</creationdate><title>BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins</title><author>Weber, Arnim ; 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Current models assume that apoptosis induction occurs via the binding and inactivation of anti-apoptotic Bcl-2 proteins by BH3-only proteins or by direct binding to Bax. Here, we analyze apoptosis induction by the BH3-only protein Bim(S). Regulated expression of Bim(S) in epithelial cells was followed by its rapid mitochondrial translocation and mitochondrial membrane insertion in the absence of detectable binding to anti-apoptotic Bcl-2 proteins. This caused mitochondrial recruitment and activation of Bax and apoptosis. Mutational analysis of Bim(S) showed that mitochondrial targeting, but not binding to Bcl-2 or Mcl-1, was required for apoptosis induction. In yeast, Bim(S) enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins. 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| subjects | Animals Apoptosis - physiology Apoptosis Regulatory Proteins - biosynthesis Apoptosis Regulatory Proteins - metabolism Apoptosis Regulatory Proteins - physiology bcl-2-Associated X Protein - metabolism Bcl-2-Like Protein 11 Cytosol - metabolism HeLa Cells Humans Membrane Proteins - biosynthesis Membrane Proteins - metabolism Membrane Proteins - physiology Mice Mitochondria - metabolism Mitochondrial Membranes - metabolism Protein Binding Protein Transport Proto-Oncogene Proteins - biosynthesis Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins - physiology Proto-Oncogene Proteins c-bcl-2 - metabolism Proto-Oncogene Proteins c-bcl-2 - physiology |
| title | BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins |
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