A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells.
Secretory cells in glands and the nervous system frequently package and store proteins destined for regulated secretion in dense-core granules (DCGs), which disperse when released from the cell surface. Despite the relevance of this dynamic process to diseases such as diabetes and human neurodegener...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-10-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010979&type=printable |
| _version_ | 1797262978100232192 |
|---|---|
| author | Adam Wells Cláudia C Mendes Felix Castellanos Phoebe Mountain Tia Wright S Mark Wainwright M Irina Stefana Adrian L Harris Deborah C I Goberdhan Clive Wilson |
| author_facet | Adam Wells Cláudia C Mendes Felix Castellanos Phoebe Mountain Tia Wright S Mark Wainwright M Irina Stefana Adrian L Harris Deborah C I Goberdhan Clive Wilson |
| author_sort | Adam Wells |
| collection | DOAJ |
| description | Secretory cells in glands and the nervous system frequently package and store proteins destined for regulated secretion in dense-core granules (DCGs), which disperse when released from the cell surface. Despite the relevance of this dynamic process to diseases such as diabetes and human neurodegenerative disorders, our mechanistic understanding is relatively limited, because of the lack of good cell models to follow the nanoscale events involved. Here, we employ the prostate-like secondary cells (SCs) of the Drosophila male accessory gland to dissect the cell biology and genetics of DCG biogenesis. These cells contain unusually enlarged DCGs, which are assembled in compartments that also form secreted nanovesicles called exosomes. We demonstrate that known conserved regulators of DCG biogenesis, including the small G-protein Arf1 and the coatomer complex AP-1, play key roles in making SC DCGs. Using real-time imaging, we find that the aggregation events driving DCG biogenesis are accompanied by a change in the membrane-associated small Rab GTPases which are major regulators of membrane and protein trafficking in the secretory and endosomal systems. Indeed, a transition from trans-Golgi Rab6 to recycling endosomal protein Rab11, which requires conserved DCG regulators like AP-1, is essential for DCG and exosome biogenesis. Our data allow us to develop a model for DCG biogenesis that brings together several previously disparate observations concerning this process and highlights the importance of communication between the secretory and endosomal systems in controlling regulated secretion. |
| first_indexed | 2024-03-08T01:59:36Z |
| format | Article |
| id | doaj.art-3a0376c416114f0cba80597cd7bc3c26 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-25T00:05:42Z |
| publishDate | 2023-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-3a0376c416114f0cba80597cd7bc3c262024-03-14T05:31:36ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-10-011910e101097910.1371/journal.pgen.1010979A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells.Adam WellsCláudia C MendesFelix CastellanosPhoebe MountainTia WrightS Mark WainwrightM Irina StefanaAdrian L HarrisDeborah C I GoberdhanClive WilsonSecretory cells in glands and the nervous system frequently package and store proteins destined for regulated secretion in dense-core granules (DCGs), which disperse when released from the cell surface. Despite the relevance of this dynamic process to diseases such as diabetes and human neurodegenerative disorders, our mechanistic understanding is relatively limited, because of the lack of good cell models to follow the nanoscale events involved. Here, we employ the prostate-like secondary cells (SCs) of the Drosophila male accessory gland to dissect the cell biology and genetics of DCG biogenesis. These cells contain unusually enlarged DCGs, which are assembled in compartments that also form secreted nanovesicles called exosomes. We demonstrate that known conserved regulators of DCG biogenesis, including the small G-protein Arf1 and the coatomer complex AP-1, play key roles in making SC DCGs. Using real-time imaging, we find that the aggregation events driving DCG biogenesis are accompanied by a change in the membrane-associated small Rab GTPases which are major regulators of membrane and protein trafficking in the secretory and endosomal systems. Indeed, a transition from trans-Golgi Rab6 to recycling endosomal protein Rab11, which requires conserved DCG regulators like AP-1, is essential for DCG and exosome biogenesis. Our data allow us to develop a model for DCG biogenesis that brings together several previously disparate observations concerning this process and highlights the importance of communication between the secretory and endosomal systems in controlling regulated secretion.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010979&type=printable |
| spellingShingle | Adam Wells Cláudia C Mendes Felix Castellanos Phoebe Mountain Tia Wright S Mark Wainwright M Irina Stefana Adrian L Harris Deborah C I Goberdhan Clive Wilson A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells. PLoS Genetics |
| title | A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells. |
| title_full | A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells. |
| title_fullStr | A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells. |
| title_full_unstemmed | A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells. |
| title_short | A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells. |
| title_sort | rab6 to rab11 transition is required for dense core granule and exosome biogenesis in drosophila secondary cells |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010979&type=printable |
| work_keys_str_mv | AT adamwells arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT claudiacmendes arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT felixcastellanos arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT phoebemountain arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT tiawright arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT smarkwainwright arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT mirinastefana arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT adrianlharris arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT deborahcigoberdhan arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT clivewilson arab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT adamwells rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT claudiacmendes rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT felixcastellanos rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT phoebemountain rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT tiawright rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT smarkwainwright rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT mirinastefana rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT adrianlharris rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT deborahcigoberdhan rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells AT clivewilson rab6torab11transitionisrequiredfordensecoregranuleandexosomebiogenesisindrosophilasecondarycells |