Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the <i>FUS</i> gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FT...
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2025-01-01
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| author | Seth A. Bennett Samantha N. Cobos Raven M. A. Fisher Elizaveta Son Rania Frederic Rianna Segal Huda Yousuf Kaitlyn Chan David K. Dansu Mariana P. Torrente |
| author_facet | Seth A. Bennett Samantha N. Cobos Raven M. A. Fisher Elizaveta Son Rania Frederic Rianna Segal Huda Yousuf Kaitlyn Chan David K. Dansu Mariana P. Torrente |
| author_sort | Seth A. Bennett |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the <i>FUS</i> gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109—responsible for installing H3S10ph and H3K56ac—are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention. |
| format | Article |
| id | doaj-art-2d93844f63514fbb98def5b6d6d7f416 |
| institution | Kabale University |
| issn | 2309-608X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Journal of Fungi |
| spelling | doaj-art-2d93844f63514fbb98def5b6d6d7f4162025-01-24T13:37:23ZengMDPI AGJournal of Fungi2309-608X2025-01-011115810.3390/jof11010058Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast ModelSeth A. Bennett0Samantha N. Cobos1Raven M. A. Fisher2Elizaveta Son3Rania Frederic4Rianna Segal5Huda Yousuf6Kaitlyn Chan7David K. Dansu8Mariana P. Torrente9Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USAPh.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USADepartment of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USAAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the <i>FUS</i> gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109—responsible for installing H3S10ph and H3K56ac—are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.https://www.mdpi.com/2309-608X/11/1/58FUSamyotrophic lateral sclerosisfrontotemporal dementiaepigeneticshistone post-translational modificationsIpl1 |
| spellingShingle | Seth A. Bennett Samantha N. Cobos Raven M. A. Fisher Elizaveta Son Rania Frederic Rianna Segal Huda Yousuf Kaitlyn Chan David K. Dansu Mariana P. Torrente Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model Journal of Fungi FUS amyotrophic lateral sclerosis frontotemporal dementia epigenetics histone post-translational modifications Ipl1 |
| title | Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model |
| title_full | Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model |
| title_fullStr | Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model |
| title_full_unstemmed | Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model |
| title_short | Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model |
| title_sort | direct and indirect protein interactions link fus aggregation to histone post translational modification dysregulation and growth suppression in an als ftd yeast model |
| topic | FUS amyotrophic lateral sclerosis frontotemporal dementia epigenetics histone post-translational modifications Ipl1 |
| url | https://www.mdpi.com/2309-608X/11/1/58 |
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