A fast-acting lipid checkpoint in G1 prevents mitotic defects
Abstract Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and tran...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46696-9 |
| _version_ | 1827310060799262720 |
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| author | Marielle S. Köberlin Yilin Fan Chad Liu Mingyu Chung Antonio F. M. Pinto Peter K. Jackson Alan Saghatelian Tobias Meyer |
| author_facet | Marielle S. Köberlin Yilin Fan Chad Liu Mingyu Chung Antonio F. M. Pinto Peter K. Jackson Alan Saghatelian Tobias Meyer |
| author_sort | Marielle S. Köberlin |
| collection | DOAJ |
| description | Abstract Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis. |
| first_indexed | 2024-04-24T19:53:41Z |
| format | Article |
| id | doaj.art-46284f4c6c074cc8a607922f662f2987 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T19:53:41Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-46284f4c6c074cc8a607922f662f29872024-03-24T12:27:08ZengNature PortfolioNature Communications2041-17232024-03-0115111710.1038/s41467-024-46696-9A fast-acting lipid checkpoint in G1 prevents mitotic defectsMarielle S. Köberlin0Yilin Fan1Chad Liu2Mingyu Chung3Antonio F. M. Pinto4Peter K. Jackson5Alan Saghatelian6Tobias Meyer7Department of Chemical and Systems Biology, Stanford University School of MedicineDepartment of Chemical and Systems Biology, Stanford University School of MedicineDepartment of Chemical and Systems Biology, Stanford University School of MedicineDepartment of Chemical and Systems Biology, Stanford University School of MedicineClayton Foundation Laboratories for Peptide Biology and Mass Spectrometry Core, Salk Institute for Biological StudiesBaxter Laboratory, Department of Microbiology & Immunology, Stanford University School of MedicineClayton Foundation Laboratories for Peptide Biology and Mass Spectrometry Core, Salk Institute for Biological StudiesDepartment of Chemical and Systems Biology, Stanford University School of MedicineAbstract Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.https://doi.org/10.1038/s41467-024-46696-9 |
| spellingShingle | Marielle S. Köberlin Yilin Fan Chad Liu Mingyu Chung Antonio F. M. Pinto Peter K. Jackson Alan Saghatelian Tobias Meyer A fast-acting lipid checkpoint in G1 prevents mitotic defects Nature Communications |
| title | A fast-acting lipid checkpoint in G1 prevents mitotic defects |
| title_full | A fast-acting lipid checkpoint in G1 prevents mitotic defects |
| title_fullStr | A fast-acting lipid checkpoint in G1 prevents mitotic defects |
| title_full_unstemmed | A fast-acting lipid checkpoint in G1 prevents mitotic defects |
| title_short | A fast-acting lipid checkpoint in G1 prevents mitotic defects |
| title_sort | fast acting lipid checkpoint in g1 prevents mitotic defects |
| url | https://doi.org/10.1038/s41467-024-46696-9 |
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