VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo
Lysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosom...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2015-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/07366 |
| _version_ | 1818019696185704448 |
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| author | Alyssa E Johnson Huidy Shu Anna G Hauswirth Amy Tong Graeme W Davis |
| author_facet | Alyssa E Johnson Huidy Shu Anna G Hauswirth Amy Tong Graeme W Davis |
| author_sort | Alyssa E Johnson |
| collection | DOAJ |
| description | Lysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosomal membranes undergo extension, retraction, fusion and fission. The dynamics and integrity of this tubular lysosomal network requires VCP, an AAA-ATPase that, when mutated, causes degenerative diseases of muscle, bone and neurons. We show that human VCP rescues the defects caused by loss of Drosophila VCP and overexpression of disease relevant VCP transgenes dismantles tubular lysosomes, linking tubular lysosome dysfunction to human VCP-related diseases. Finally, disruption of tubular lysosomes correlates with impaired autophagosome-lysosome fusion, increased cytoplasmic poly-ubiquitin aggregates, lipofuscin material, damaged mitochondria and impaired muscle function. We propose that VCP sustains sarcoplasmic proteostasis, in part, by controlling the integrity of a dynamic tubular lysosomal network. |
| first_indexed | 2024-04-14T07:55:47Z |
| format | Article |
| id | doaj.art-7c0e6c2046194465a423afc43aee993f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:55:47Z |
| publishDate | 2015-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7c0e6c2046194465a423afc43aee993f2022-12-22T02:05:04ZengeLife Sciences Publications LtdeLife2050-084X2015-07-01410.7554/eLife.07366VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivoAlyssa E Johnson0Huidy Shu1Anna G Hauswirth2Amy Tong3Graeme W Davis4Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesLysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosomal membranes undergo extension, retraction, fusion and fission. The dynamics and integrity of this tubular lysosomal network requires VCP, an AAA-ATPase that, when mutated, causes degenerative diseases of muscle, bone and neurons. We show that human VCP rescues the defects caused by loss of Drosophila VCP and overexpression of disease relevant VCP transgenes dismantles tubular lysosomes, linking tubular lysosome dysfunction to human VCP-related diseases. Finally, disruption of tubular lysosomes correlates with impaired autophagosome-lysosome fusion, increased cytoplasmic poly-ubiquitin aggregates, lipofuscin material, damaged mitochondria and impaired muscle function. We propose that VCP sustains sarcoplasmic proteostasis, in part, by controlling the integrity of a dynamic tubular lysosomal network.https://elifesciences.org/articles/07366autophagylysosomeskeletal muscleIBMPFDamyotrophic lateral sclerosisspinster |
| spellingShingle | Alyssa E Johnson Huidy Shu Anna G Hauswirth Amy Tong Graeme W Davis VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo eLife autophagy lysosome skeletal muscle IBMPFD amyotrophic lateral sclerosis spinster |
| title | VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo |
| title_full | VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo |
| title_fullStr | VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo |
| title_full_unstemmed | VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo |
| title_short | VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo |
| title_sort | vcp dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo |
| topic | autophagy lysosome skeletal muscle IBMPFD amyotrophic lateral sclerosis spinster |
| url | https://elifesciences.org/articles/07366 |
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