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Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously u...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691453/ https://www.ncbi.nlm.nih.gov/pubmed/23798729 http://dx.doi.org/10.1083/jcb.201210045 |
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author | Strack, Stefan Wilson, Theodore J. Cribbs, J. Thomas |
author_facet | Strack, Stefan Wilson, Theodore J. Cribbs, J. Thomas |
author_sort | Strack, Stefan |
collection | PubMed |
description | Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1-x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form–specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin-dependent kinase signaling. |
format | Online Article Text |
id | pubmed-3691453 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-36914532013-12-24 Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules Strack, Stefan Wilson, Theodore J. Cribbs, J. Thomas J Cell Biol Research Articles Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1-x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form–specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin-dependent kinase signaling. The Rockefeller University Press 2013-06-24 /pmc/articles/PMC3691453/ /pubmed/23798729 http://dx.doi.org/10.1083/jcb.201210045 Text en © 2013 Strack et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Strack, Stefan Wilson, Theodore J. Cribbs, J. Thomas Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules |
title | Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules |
title_full | Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules |
title_fullStr | Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules |
title_full_unstemmed | Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules |
title_short | Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules |
title_sort | cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691453/ https://www.ncbi.nlm.nih.gov/pubmed/23798729 http://dx.doi.org/10.1083/jcb.201210045 |
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