A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress
Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by acinus (acn) and the Cdk5-dependent phosphorylation of its...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/72169 |
| _version_ | 1797998431852036096 |
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| author | Nilay Nandi Zuhair Zaidi Charles Tracy Helmut Krämer |
| author_facet | Nilay Nandi Zuhair Zaidi Charles Tracy Helmut Krämer |
| author_sort | Nilay Nandi |
| collection | DOAJ |
| description | Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by acinus (acn) and the Cdk5-dependent phosphorylation of its serine437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of acinus-serine437 (acn-S437) phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an acn gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-acn levels. Cdk5-dependent phosphorylation of acn-S437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington’s disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+ exposure elevated acn-S437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the acn-S437 phosphoswitch as critical integrator of multiple stress signals regulating neuronal autophagy. |
| first_indexed | 2024-04-11T10:48:40Z |
| format | Article |
| id | doaj.art-4190de0e76464f52957de259919c3aa3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:48:40Z |
| publishDate | 2022-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4190de0e76464f52957de259919c3aa32022-12-22T04:28:58ZengeLife Sciences Publications LtdeLife2050-084X2022-01-011110.7554/eLife.72169A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stressNilay Nandi0https://orcid.org/0000-0002-7088-4943Zuhair Zaidi1Charles Tracy2https://orcid.org/0000-0001-7769-4950Helmut Krämer3https://orcid.org/0000-0002-1167-2676Department of Neuroscience, UT Southwestern Medical Center, Dallas, United StatesDepartment of Neuroscience, UT Southwestern Medical Center, Dallas, United StatesDepartment of Neuroscience, UT Southwestern Medical Center, Dallas, United StatesDepartment of Neuroscience, UT Southwestern Medical Center, Dallas, United States; Department of Cell Biology, UT Southwestern Medical Center, Dallas, United StatesNeuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by acinus (acn) and the Cdk5-dependent phosphorylation of its serine437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of acinus-serine437 (acn-S437) phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an acn gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-acn levels. Cdk5-dependent phosphorylation of acn-S437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington’s disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+ exposure elevated acn-S437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the acn-S437 phosphoswitch as critical integrator of multiple stress signals regulating neuronal autophagy.https://elifesciences.org/articles/72169autophagyproteostasisphosphatasescadmium |
| spellingShingle | Nilay Nandi Zuhair Zaidi Charles Tracy Helmut Krämer A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress eLife autophagy proteostasis phosphatases cadmium |
| title | A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress |
| title_full | A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress |
| title_fullStr | A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress |
| title_full_unstemmed | A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress |
| title_short | A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress |
| title_sort | phosphoswitch at acinus serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress |
| topic | autophagy proteostasis phosphatases cadmium |
| url | https://elifesciences.org/articles/72169 |
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