The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy
Drosophila blue cheese (bchs) encodes a BEACH domain adaptor protein that, like its human homolog ALFY, promotes clearance of aggregated proteins through its interaction with Atg5 and p62. bchs mutations lead to age-dependent accumulation of ubiquitinated inclusions and progressive neurodegeneration...
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sg-ntu-dr.10356-1421012023-02-28T16:56:55Z The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy Sim, Joan Osborne, Kathleen Amy García, Irene Argudo Matysik, Artur Stanislaw Kraut, Rachel School of Biological Sciences Singapore Centre for Environmental Life Sciences and Engineering Science::Biological sciences Blue Cheese Drosophila Drosophila blue cheese (bchs) encodes a BEACH domain adaptor protein that, like its human homolog ALFY, promotes clearance of aggregated proteins through its interaction with Atg5 and p62. bchs mutations lead to age-dependent accumulation of ubiquitinated inclusions and progressive neurodegeneration in the fly brain, but neither the influence of autophagy on bchs-related degeneration, nor bchs’ placement in the autophagic hierarchy have been shown. We present epistatic evidence in a well-defined larval motor neuron paradigm that in bchs mutants, synaptic accumulation of ubiquitinated aggregates and neuronal death can be rescued by pharmacologically amplifying autophagic initiation. Further, pharmacological rescue requires at least one intact BEACH-containing isoform of the two identified in this study. Genetically augmenting a late step in autophagy, however, rescues even a strong mutation which retains only a third, non-BEACH containing isoform. Using living primary larval brain neurons, we elucidate the primary defect in bchs to be an excess of early autophagic compartments and a deficit in mature compartments. Conversely, rescuing the mutants by full-length Bchs over-expression induces mature compartment proliferation and rescues neuronal death. Surprisingly, only the longest Bchs isoform colocalizes well with autophagosomes, and shuttles between different vesicular locations depending on the type of autophagic impetus applied. Our results are consistent with Bchs promoting autophagic maturation, and the BEACH domain being required for this function. MOE (Min. of Education, S’pore) Published version 2020-06-16T01:37:10Z 2020-06-16T01:37:10Z 2019 Journal Article Sim, J., Osborne, K. A., García, I. A., Matysik, A. S., & Kraut, R. (2019). The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy. Frontiers in Cell and Developmental Biology, 7, 129-. doi:10.3389/fcell.2019.00129 2296-634X https://hdl.handle.net/10356/142101 10.3389/fcell.2019.00129 31428609 2-s2.0-85072731084 7 en Frontiers in Cell and Developmental Biology © 2019 Sim, Osborne, Argudo García, Matysik and Kraut. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. application/pdf |
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Science::Biological sciences Blue Cheese Drosophila Sim, Joan Osborne, Kathleen Amy García, Irene Argudo Matysik, Artur Stanislaw Kraut, Rachel The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy |
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Drosophila blue cheese (bchs) encodes a BEACH domain adaptor protein that, like its human homolog ALFY, promotes clearance of aggregated proteins through its interaction with Atg5 and p62. bchs mutations lead to age-dependent accumulation of ubiquitinated inclusions and progressive neurodegeneration in the fly brain, but neither the influence of autophagy on bchs-related degeneration, nor bchs’ placement in the autophagic hierarchy have been shown. We present epistatic evidence in a well-defined larval motor neuron paradigm that in bchs mutants, synaptic accumulation of ubiquitinated aggregates and neuronal death can be rescued by pharmacologically amplifying autophagic initiation. Further, pharmacological rescue requires at least one intact BEACH-containing isoform of the two identified in this study. Genetically augmenting a late step in autophagy, however, rescues even a strong mutation which retains only a third, non-BEACH containing isoform. Using living primary larval brain neurons, we elucidate the primary defect in bchs to be an excess of early autophagic compartments and a deficit in mature compartments. Conversely, rescuing the mutants by full-length Bchs over-expression induces mature compartment proliferation and rescues neuronal death. Surprisingly, only the longest Bchs isoform colocalizes well with autophagosomes, and shuttles between different vesicular locations depending on the type of autophagic impetus applied. Our results are consistent with Bchs promoting autophagic maturation, and the BEACH domain being required for this function. |
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School of Biological Sciences |
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School of Biological Sciences Sim, Joan Osborne, Kathleen Amy García, Irene Argudo Matysik, Artur Stanislaw Kraut, Rachel |
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Article |
author |
Sim, Joan Osborne, Kathleen Amy García, Irene Argudo Matysik, Artur Stanislaw Kraut, Rachel |
author_sort |
Sim, Joan |
title |
The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy |
title_short |
The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy |
title_full |
The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy |
title_fullStr |
The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy |
title_full_unstemmed |
The BEACH domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy |
title_sort |
beach domain is critical for blue cheese function in a spatial and epistatic autophagy hierarchy |
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2020 |
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https://hdl.handle.net/10356/142101 |
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1759856806712049664 |