The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy
Summary: The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report characterization of a viable knockout model of PRP4K in the social amoeba Dictyostelium discoideum, revealing a function for PRP4K in splic...
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| Language: | English |
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Elsevier
2025-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725006412 |
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| author | Sabateeshan Mathavarajah Sandhya Chipurupalli Elias B. Habib William D. Kim Megan M. Aoki Dale P. Corkery Kennedy I.T. Whelan Jordan Lukacs Melis Erkan Victor D. Martinez Kevin S. Smith Stephen B. Montgomery Jayme Salsman Robert J. Huber Graham Dellaire |
| author_facet | Sabateeshan Mathavarajah Sandhya Chipurupalli Elias B. Habib William D. Kim Megan M. Aoki Dale P. Corkery Kennedy I.T. Whelan Jordan Lukacs Melis Erkan Victor D. Martinez Kevin S. Smith Stephen B. Montgomery Jayme Salsman Robert J. Huber Graham Dellaire |
| author_sort | Sabateeshan Mathavarajah |
| collection | DOAJ |
| description | Summary: The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report characterization of a viable knockout model of PRP4K in the social amoeba Dictyostelium discoideum, revealing a function for PRP4K in splicing events controlling autophagy. When prp4k knockout amoebae undergo multicellular development, we observe defects in differentiation linked to abnormal autophagy and aberrant secretion of stalk cell inducer c-di-GMP. Autophagosome-lysosome fusion is impaired after PRP4K loss in both human cell lines and amoebae. PRP4K loss results in mis-splicing and reduced expression of the ESCRT-III gene CHMP4B in human cells and its ortholog vps32 in Dictyostelium, and re-expression of CHMP4B or Vps32 cDNA (respectively) restores normal autophagosome-lysosome fusion in PRP4K-deficient cells. Thus, our work reveals a PRP4K-CHMP4B/vps32 splicing circuit regulating autophagy that is conserved over at least 600 million years of evolution. |
| format | Article |
| id | doaj-art-9cf4ccb924474954a56519ea6c7c9d5a |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-9cf4ccb924474954a56519ea6c7c9d5a2025-08-20T02:07:35ZengElsevierCell Reports2211-12472025-07-0144711587010.1016/j.celrep.2025.115870The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagySabateeshan Mathavarajah0Sandhya Chipurupalli1Elias B. Habib2William D. Kim3Megan M. Aoki4Dale P. Corkery5Kennedy I.T. Whelan6Jordan Lukacs7Melis Erkan8Victor D. Martinez9Kevin S. Smith10Stephen B. Montgomery11Jayme Salsman12Robert J. Huber13Graham Dellaire14Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, CanadaDepartment of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, CanadaDepartment of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, CanadaDepartment of Biology, Trent University, Peterborough, ON K9L 0G2, CanadaDepartment of Biology, Trent University, Peterborough, ON K9L 0G2, CanadaDepartment of Chemistry, Umeå University, Umeå SE-90187, SwedenDepartment of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, CanadaDepartment of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, CanadaDepartment of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; Department of Pathology and Laboratory Medicine, IWK Health Centre, Halifax, NS B3K 6R8, CanadaDepartment of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; Department of Pathology and Laboratory Medicine, IWK Health Centre, Halifax, NS B3K 6R8, CanadaDepartments of Genetics and Pathology, Stanford University, Stanford, CA 94305, USADepartments of Genetics and Pathology, Stanford University, Stanford, CA 94305, USADepartment of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, CanadaDepartment of Biology, Trent University, Peterborough, ON K9L 0G2, Canada; Corresponding authorDepartment of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada; Corresponding authorSummary: The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report characterization of a viable knockout model of PRP4K in the social amoeba Dictyostelium discoideum, revealing a function for PRP4K in splicing events controlling autophagy. When prp4k knockout amoebae undergo multicellular development, we observe defects in differentiation linked to abnormal autophagy and aberrant secretion of stalk cell inducer c-di-GMP. Autophagosome-lysosome fusion is impaired after PRP4K loss in both human cell lines and amoebae. PRP4K loss results in mis-splicing and reduced expression of the ESCRT-III gene CHMP4B in human cells and its ortholog vps32 in Dictyostelium, and re-expression of CHMP4B or Vps32 cDNA (respectively) restores normal autophagosome-lysosome fusion in PRP4K-deficient cells. Thus, our work reveals a PRP4K-CHMP4B/vps32 splicing circuit regulating autophagy that is conserved over at least 600 million years of evolution.http://www.sciencedirect.com/science/article/pii/S2211124725006412CP: Cell biologyCP: Developmental biology |
| spellingShingle | Sabateeshan Mathavarajah Sandhya Chipurupalli Elias B. Habib William D. Kim Megan M. Aoki Dale P. Corkery Kennedy I.T. Whelan Jordan Lukacs Melis Erkan Victor D. Martinez Kevin S. Smith Stephen B. Montgomery Jayme Salsman Robert J. Huber Graham Dellaire The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy Cell Reports CP: Cell biology CP: Developmental biology |
| title | The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy |
| title_full | The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy |
| title_fullStr | The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy |
| title_full_unstemmed | The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy |
| title_short | The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy |
| title_sort | evolutionarily conserved prp4k chmp4b vps32 splicing circuit regulates autophagy |
| topic | CP: Cell biology CP: Developmental biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725006412 |
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