Ibetazol, a novel inhibitor of importin β1-mediated nuclear import
Abstract Nucleocytoplasmatic transport plays an essential role in eukaryotic cell homeostasis and is mediated by karyopherins. Importin β1 (KPNB1) and its adaptor protein importin α1 (KPNA2) are the best-characterized karyopherins that effect nuclear import. Here, we identify a novel small-molecule...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07237-8 |
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| author | Thomas Vercruysse Els Vanstreels Maarten Jacquemyn Sandro Boland Amuri Kilonda Sara Allasia Ilse Vandecaetsbeek Hugo Klaassen Matthias Versele Patrick Chaltin Arnaud Marchand Dirk Daelemans |
| author_facet | Thomas Vercruysse Els Vanstreels Maarten Jacquemyn Sandro Boland Amuri Kilonda Sara Allasia Ilse Vandecaetsbeek Hugo Klaassen Matthias Versele Patrick Chaltin Arnaud Marchand Dirk Daelemans |
| author_sort | Thomas Vercruysse |
| collection | DOAJ |
| description | Abstract Nucleocytoplasmatic transport plays an essential role in eukaryotic cell homeostasis and is mediated by karyopherins. Importin β1 (KPNB1) and its adaptor protein importin α1 (KPNA2) are the best-characterized karyopherins that effect nuclear import. Here, we identify a novel small-molecule inhibitor of the importin β1-mediated nuclear import. We design a reporter cell line by stably tagging endogenous importin α1 with a fluorescent protein to screen for compounds affecting its subcellular localization. We identify a series of compounds that trigger cytoplasmatic accumulation of importin α1. The lead compound, ibetazol, is further characterized in a broad sequence of cellular nuclear transport assays. Ibetazol is shown to inhibit all importin β1-mediated nuclear import quickly and specifically, without affecting transport mediated by other karyopherins. Detailed molecular mechanism of action studies demonstrate that ibetazol inhibits importin β1 by covalently targeting Cys585. In summary, ibetazol is a novel small molecule inhibitor of importin β1 enabling pharmacological inhibition of the importin β1-mediated nuclear import process with wide applicability in different fields. |
| format | Article |
| id | doaj-art-6d5b372d2108496cbb7b665ef0f808a6 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-6d5b372d2108496cbb7b665ef0f808a62024-11-24T12:39:04ZengNature PortfolioCommunications Biology2399-36422024-11-017111410.1038/s42003-024-07237-8Ibetazol, a novel inhibitor of importin β1-mediated nuclear importThomas Vercruysse0Els Vanstreels1Maarten Jacquemyn2Sandro Boland3Amuri Kilonda4Sara Allasia5Ilse Vandecaetsbeek6Hugo Klaassen7Matthias Versele8Patrick Chaltin9Arnaud Marchand10Dirk Daelemans11KU Leuven Department of Microbiology, Immunology and Transplantation, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Rega InstituteKU Leuven Department of Microbiology, Immunology and Transplantation, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Rega InstituteKU Leuven Department of Microbiology, Immunology and Transplantation, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Rega InstituteCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwKU Leuven Department of Microbiology, Immunology and Transplantation, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Rega InstituteAbstract Nucleocytoplasmatic transport plays an essential role in eukaryotic cell homeostasis and is mediated by karyopherins. Importin β1 (KPNB1) and its adaptor protein importin α1 (KPNA2) are the best-characterized karyopherins that effect nuclear import. Here, we identify a novel small-molecule inhibitor of the importin β1-mediated nuclear import. We design a reporter cell line by stably tagging endogenous importin α1 with a fluorescent protein to screen for compounds affecting its subcellular localization. We identify a series of compounds that trigger cytoplasmatic accumulation of importin α1. The lead compound, ibetazol, is further characterized in a broad sequence of cellular nuclear transport assays. Ibetazol is shown to inhibit all importin β1-mediated nuclear import quickly and specifically, without affecting transport mediated by other karyopherins. Detailed molecular mechanism of action studies demonstrate that ibetazol inhibits importin β1 by covalently targeting Cys585. In summary, ibetazol is a novel small molecule inhibitor of importin β1 enabling pharmacological inhibition of the importin β1-mediated nuclear import process with wide applicability in different fields.https://doi.org/10.1038/s42003-024-07237-8 |
| spellingShingle | Thomas Vercruysse Els Vanstreels Maarten Jacquemyn Sandro Boland Amuri Kilonda Sara Allasia Ilse Vandecaetsbeek Hugo Klaassen Matthias Versele Patrick Chaltin Arnaud Marchand Dirk Daelemans Ibetazol, a novel inhibitor of importin β1-mediated nuclear import Communications Biology |
| title | Ibetazol, a novel inhibitor of importin β1-mediated nuclear import |
| title_full | Ibetazol, a novel inhibitor of importin β1-mediated nuclear import |
| title_fullStr | Ibetazol, a novel inhibitor of importin β1-mediated nuclear import |
| title_full_unstemmed | Ibetazol, a novel inhibitor of importin β1-mediated nuclear import |
| title_short | Ibetazol, a novel inhibitor of importin β1-mediated nuclear import |
| title_sort | ibetazol a novel inhibitor of importin β1 mediated nuclear import |
| url | https://doi.org/10.1038/s42003-024-07237-8 |
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