Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond
Protein mislocalization and aggregation are hallmark features in neurodegeneration. As proteins mislocalize, proteostasis deficiency and protein aggregation typically follow. Autophagy is a crucial pathway for the removal of protein aggregates to maintain neuronal health, but is impaired in various...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Autophagy Reports |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/27694127.2025.2547975 |
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| author | Y Alshehabi F Abrar D.D.O Martin |
| author_facet | Y Alshehabi F Abrar D.D.O Martin |
| author_sort | Y Alshehabi |
| collection | DOAJ |
| description | Protein mislocalization and aggregation are hallmark features in neurodegeneration. As proteins mislocalize, proteostasis deficiency and protein aggregation typically follow. Autophagy is a crucial pathway for the removal of protein aggregates to maintain neuronal health, but is impaired in various neurodegenerative diseases, including Huntington disease (HD). We identified S-acylation, a reversible lipid modification of proteins, as an important regulator in protein trafficking and autophagy. SQSTM1 (sequestosome 1/p62) is an essential selective autophagy receptor for the sequestration of ubiquitinated cargoes within autophagosomes and subsequent delivery into lysosomes for degradation. Recently, we reported that S-acylation of SQSTM1 at the di-cysteine motif C289,290 directs SQSTM1 to lysosomes. We further showed that SQSTM1 S-acylation is significantly reduced in brains from both HD patients and mouse HD model, which may result in the cargo sequestration defect within autophagosomes in HD. Treatment with palmostatin B, a deacylation inhibitor, significantly increases SQSTM1 localization to lysosomes. Our work highlights SQSTM1 S-acylation as a novel potential therapeutic strategy in HD. As a crucial autophagy component, our work suggests S-acylation of SQSTM1 may have a broader role in neurodegeneration. |
| format | Article |
| id | doaj-art-ef9dd5b54279478896fdda8a56ff5ceb |
| institution | Kabale University |
| issn | 2769-4127 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj-art-ef9dd5b54279478896fdda8a56ff5ceb2025-08-25T12:09:52ZengTaylor & Francis GroupAutophagy Reports2769-41272025-12-014110.1080/27694127.2025.2547975Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyondY Alshehabi0F Abrar1D.D.O Martin2Department of Biology, University of Waterloo, Waterloo, ON, CanadaDepartment of Biology, University of Waterloo, Waterloo, ON, CanadaDepartment of Biology, University of Waterloo, Waterloo, ON, CanadaProtein mislocalization and aggregation are hallmark features in neurodegeneration. As proteins mislocalize, proteostasis deficiency and protein aggregation typically follow. Autophagy is a crucial pathway for the removal of protein aggregates to maintain neuronal health, but is impaired in various neurodegenerative diseases, including Huntington disease (HD). We identified S-acylation, a reversible lipid modification of proteins, as an important regulator in protein trafficking and autophagy. SQSTM1 (sequestosome 1/p62) is an essential selective autophagy receptor for the sequestration of ubiquitinated cargoes within autophagosomes and subsequent delivery into lysosomes for degradation. Recently, we reported that S-acylation of SQSTM1 at the di-cysteine motif C289,290 directs SQSTM1 to lysosomes. We further showed that SQSTM1 S-acylation is significantly reduced in brains from both HD patients and mouse HD model, which may result in the cargo sequestration defect within autophagosomes in HD. Treatment with palmostatin B, a deacylation inhibitor, significantly increases SQSTM1 localization to lysosomes. Our work highlights SQSTM1 S-acylation as a novel potential therapeutic strategy in HD. As a crucial autophagy component, our work suggests S-acylation of SQSTM1 may have a broader role in neurodegeneration.https://www.tandfonline.com/doi/10.1080/27694127.2025.2547975AutophagyS-acylationpalmitoylationpalmostatin BHuntington diseasesequestosome 1 |
| spellingShingle | Y Alshehabi F Abrar D.D.O Martin Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond Autophagy Reports Autophagy S-acylation palmitoylation palmostatin B Huntington disease sequestosome 1 |
| title | Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond |
| title_full | Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond |
| title_fullStr | Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond |
| title_full_unstemmed | Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond |
| title_short | Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond |
| title_sort | sequestering sequestosome 1 via s acylation in autophagy huntington disease and beyond |
| topic | Autophagy S-acylation palmitoylation palmostatin B Huntington disease sequestosome 1 |
| url | https://www.tandfonline.com/doi/10.1080/27694127.2025.2547975 |
| work_keys_str_mv | AT yalshehabi sequesteringsequestosome1viasacylationinautophagyhuntingtondiseaseandbeyond AT fabrar sequesteringsequestosome1viasacylationinautophagyhuntingtondiseaseandbeyond AT ddomartin sequesteringsequestosome1viasacylationinautophagyhuntingtondiseaseandbeyond |