The time course of signaling by peptide hormones, neural peptides, and other neuromodulators depends on their storage inside dense core vesicles (DCVs). Adaptor protein 3 (AP-3) assembles the membrane proteins that confer regulated release of DCVs and is thought to promote their trafficking from endosomes directly to maturing DCVs. We now find that regulated monoamine release from DCVs requires sorting nexin 5 (SNX5). Loss of SNX5 disrupts trafficking of the vesicular monoamine transporter (VMAT) to DCVs. The mechanism involves a role for SNX5 in retrograde transport of VMAT from endosomes to the TGN. However, this role for SNX5 conflicts with the proposed function of AP-3 in trafficking from endosomes directly to DCVs. We now identify a transient role for AP-3 at the TGN, where it associates with DCV cargo. Thus, retrograde transport from endosomes by SNX5 enables DCV assembly at the TGN by AP-3, resolving the apparent antagonism. A novel role for AP-3 at the TGN has implications for other organelles that also depend on this adaptor.
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2 May 2022
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April 15 2022
SNX5 targets a monoamine transporter to the TGN for assembly into dense core vesicles by AP-3
Hongfei Xu
,
Hongfei Xu
1
Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
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Fei Chang,
Fei Chang
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
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Shweta Jain,
Shweta Jain
1
Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA
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Bradley Austin Heller,
Bradley Austin Heller
1
Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA
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Xu Han,
Xu Han
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
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Yongjian Liu,
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
3
Departments of Pharmacology and Biological Chemistry, University of Pittsburgh, Pittsburgh, PA
Yongjian Liu: young.liu78@gmail.com
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Robert H. Edwards
1
Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA
Correspondence to Robert H. Edwards: robert.edwards@ucsf.edu
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Hongfei Xu
1
Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
Fei Chang
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
Shweta Jain
1
Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA
Bradley Austin Heller
1
Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA
Xu Han
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
2
Jiangsu Key Laboratory of Xenotransplantation, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
3
Departments of Pharmacology and Biological Chemistry, University of Pittsburgh, Pittsburgh, PA
Correspondence to Robert H. Edwards: robert.edwards@ucsf.edu
Yongjian Liu: young.liu78@gmail.com
Received:
June 15 2021
Revision Received:
December 06 2021
Accepted:
February 16 2022
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
National Nature Science Foundation of China
- Award Id(s): 31371436,8157051134
Funder(s):
John and Helen Cahill Family Endowed Chair
- Award Id(s): R01 MH50712,R01 NS103938
© 2022 Xu et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2022) 221 (5): e202106083.
Article history
Received:
June 15 2021
Revision Received:
December 06 2021
Accepted:
February 16 2022
Citation
Hongfei Xu, Fei Chang, Shweta Jain, Bradley Austin Heller, Xu Han, Yongjian Liu, Robert H. Edwards; SNX5 targets a monoamine transporter to the TGN for assembly into dense core vesicles by AP-3. J Cell Biol 2 May 2022; 221 (5): e202106083. doi: https://doi.org/10.1083/jcb.202106083
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