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GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin
Recent studies demonstrated that the Golgi reassembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative dis...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352920/ https://www.ncbi.nlm.nih.gov/pubmed/35780830 http://dx.doi.org/10.1016/j.jbc.2022.102219 |
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author | Ahat, Erpan Bui, Sarah Zhang, Jianchao da Veiga Leprevost, Felipe Sharkey, Lisa Reid, Whitney Nesvizhskii, Alexey I. Paulson, Henry L. Wang, Yanzhuang |
author_facet | Ahat, Erpan Bui, Sarah Zhang, Jianchao da Veiga Leprevost, Felipe Sharkey, Lisa Reid, Whitney Nesvizhskii, Alexey I. Paulson, Henry L. Wang, Yanzhuang |
author_sort | Ahat, Erpan |
collection | PubMed |
description | Recent studies demonstrated that the Golgi reassembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease–related proteins, including mutant huntingtin (Htt-Q74), superoxide dismutase 1 (SOD1), tau, and TAR DNA–binding protein 43 (TDP-43), for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55 and autophagy dependent and is enhanced under stress conditions such as starvation and endoplasmic reticulum stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the endoplasmic reticulum–Golgi intermediate compartment. Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, whereas inhibition of Htt-Q74 secretion by GRASP55 KO enhances Htt aggregation and toxicity. Finally, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including transgelin (TAGLN), multifunctional protein ADE2 (PAICS), and peroxiredoxin-1 (PRDX1). In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington’s disease. |
format | Online Article Text |
id | pubmed-9352920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-93529202022-08-09 GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin Ahat, Erpan Bui, Sarah Zhang, Jianchao da Veiga Leprevost, Felipe Sharkey, Lisa Reid, Whitney Nesvizhskii, Alexey I. Paulson, Henry L. Wang, Yanzhuang J Biol Chem Research Article Recent studies demonstrated that the Golgi reassembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease–related proteins, including mutant huntingtin (Htt-Q74), superoxide dismutase 1 (SOD1), tau, and TAR DNA–binding protein 43 (TDP-43), for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55 and autophagy dependent and is enhanced under stress conditions such as starvation and endoplasmic reticulum stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the endoplasmic reticulum–Golgi intermediate compartment. Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, whereas inhibition of Htt-Q74 secretion by GRASP55 KO enhances Htt aggregation and toxicity. Finally, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including transgelin (TAGLN), multifunctional protein ADE2 (PAICS), and peroxiredoxin-1 (PRDX1). In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington’s disease. American Society for Biochemistry and Molecular Biology 2022-07-01 /pmc/articles/PMC9352920/ /pubmed/35780830 http://dx.doi.org/10.1016/j.jbc.2022.102219 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Ahat, Erpan Bui, Sarah Zhang, Jianchao da Veiga Leprevost, Felipe Sharkey, Lisa Reid, Whitney Nesvizhskii, Alexey I. Paulson, Henry L. Wang, Yanzhuang GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin |
title | GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin |
title_full | GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin |
title_fullStr | GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin |
title_full_unstemmed | GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin |
title_short | GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin |
title_sort | grasp55 regulates the unconventional secretion and aggregation of mutant huntingtin |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352920/ https://www.ncbi.nlm.nih.gov/pubmed/35780830 http://dx.doi.org/10.1016/j.jbc.2022.102219 |
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