Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors
Abstract Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as in...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55576-1 |
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| author | Shashank Shekhar Charles Tracy Peter V. Lidsky Raul Andino Katherine J. Wert Helmut Krämer |
| author_facet | Shashank Shekhar Charles Tracy Peter V. Lidsky Raul Andino Katherine J. Wert Helmut Krämer |
| author_sort | Shashank Shekhar |
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| description | Abstract Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by eIF2αS50 phosphorylation-dependent elevated levels of the ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain. |
| format | Article |
| id | doaj-art-bee2830067624e42bb43b643bd56eb2f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-bee2830067624e42bb43b643bd56eb2f2025-01-05T12:38:01ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-55576-1Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectorsShashank Shekhar0Charles Tracy1Peter V. Lidsky2Raul Andino3Katherine J. Wert4Helmut Krämer5Department of Neuroscience, UT Southwestern Medical CenterDepartment of Neuroscience, UT Southwestern Medical CenterDepartment of Microbiology and Immunology, University of California San FranciscoDepartment of Microbiology and Immunology, University of California San FranciscoDepartment of Ophthalmology, Department of Molecular Biology, UT Southwestern Medical CenterDepartment of Neuroscience, UT Southwestern Medical CenterAbstract Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by eIF2αS50 phosphorylation-dependent elevated levels of the ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain.https://doi.org/10.1038/s41467-024-55576-1 |
| spellingShingle | Shashank Shekhar Charles Tracy Peter V. Lidsky Raul Andino Katherine J. Wert Helmut Krämer Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors Nature Communications |
| title | Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors |
| title_full | Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors |
| title_fullStr | Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors |
| title_full_unstemmed | Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors |
| title_short | Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors |
| title_sort | sensory quiescence induces a cell non autonomous integrated stress response curbed by condensate formation of the atf4 and xrp1 effectors |
| url | https://doi.org/10.1038/s41467-024-55576-1 |
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