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Identification of protein quality control regulators using a Drosophila model of TPI deficiency
Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the “common” TPI(E105D) mutation, result in reduced TPI protein stabi...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993632/ https://www.ncbi.nlm.nih.gov/pubmed/33600953 http://dx.doi.org/10.1016/j.nbd.2021.105299 |
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author | Hrizo, Stacy L. Eicher, Samantha L. Myers, Tracey D. McGrath, Ian Wodrich, Andrew P. K. Venkatesh, Hemanth Manjooran, Daniel Swoger, Sabrina Gagnon, Kim Bruskin, Matthew Lebedev, Maria V. Zheng, Sherry Vitantonio, Ana Kim, Sungyoun Lamb, Zachary J. Vogt, Andreas Ruzhnikov, Maura R.Z. Palladino, Michael J. |
author_facet | Hrizo, Stacy L. Eicher, Samantha L. Myers, Tracey D. McGrath, Ian Wodrich, Andrew P. K. Venkatesh, Hemanth Manjooran, Daniel Swoger, Sabrina Gagnon, Kim Bruskin, Matthew Lebedev, Maria V. Zheng, Sherry Vitantonio, Ana Kim, Sungyoun Lamb, Zachary J. Vogt, Andreas Ruzhnikov, Maura R.Z. Palladino, Michael J. |
author_sort | Hrizo, Stacy L. |
collection | PubMed |
description | Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the “common” TPI(E105D) mutation, result in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPI(sugarkill) allele (a.k.a. sgk or M81T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPI(sugarkill) produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPI(sugarkill) degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPI(sugarkill) degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPI(sugarkill) turnover. Of the 430 proteins screened, 25 regulators of TPI(sugarkill) were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPI(sugarkill) may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases. |
format | Online Article Text |
id | pubmed-7993632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-79936322021-05-01 Identification of protein quality control regulators using a Drosophila model of TPI deficiency Hrizo, Stacy L. Eicher, Samantha L. Myers, Tracey D. McGrath, Ian Wodrich, Andrew P. K. Venkatesh, Hemanth Manjooran, Daniel Swoger, Sabrina Gagnon, Kim Bruskin, Matthew Lebedev, Maria V. Zheng, Sherry Vitantonio, Ana Kim, Sungyoun Lamb, Zachary J. Vogt, Andreas Ruzhnikov, Maura R.Z. Palladino, Michael J. Neurobiol Dis Article Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the “common” TPI(E105D) mutation, result in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPI(sugarkill) allele (a.k.a. sgk or M81T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPI(sugarkill) produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPI(sugarkill) degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPI(sugarkill) degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPI(sugarkill) turnover. Of the 430 proteins screened, 25 regulators of TPI(sugarkill) were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPI(sugarkill) may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases. 2021-02-15 2021-05 /pmc/articles/PMC7993632/ /pubmed/33600953 http://dx.doi.org/10.1016/j.nbd.2021.105299 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Hrizo, Stacy L. Eicher, Samantha L. Myers, Tracey D. McGrath, Ian Wodrich, Andrew P. K. Venkatesh, Hemanth Manjooran, Daniel Swoger, Sabrina Gagnon, Kim Bruskin, Matthew Lebedev, Maria V. Zheng, Sherry Vitantonio, Ana Kim, Sungyoun Lamb, Zachary J. Vogt, Andreas Ruzhnikov, Maura R.Z. Palladino, Michael J. Identification of protein quality control regulators using a Drosophila model of TPI deficiency |
title | Identification of protein quality control regulators using a Drosophila model of TPI deficiency |
title_full | Identification of protein quality control regulators using a Drosophila model of TPI deficiency |
title_fullStr | Identification of protein quality control regulators using a Drosophila model of TPI deficiency |
title_full_unstemmed | Identification of protein quality control regulators using a Drosophila model of TPI deficiency |
title_short | Identification of protein quality control regulators using a Drosophila model of TPI deficiency |
title_sort | identification of protein quality control regulators using a drosophila model of tpi deficiency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993632/ https://www.ncbi.nlm.nih.gov/pubmed/33600953 http://dx.doi.org/10.1016/j.nbd.2021.105299 |
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