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  Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval

Hirst, J., Itzhak, D. N., Antrobus, R., Borner, G. H. H., & Robinson, M. S. (2018). Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval. PLoS Biology, 16(1): e2004411. doi:10.1371/journal.pbio.2004411.

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©2018 Hirst et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
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 Creators:
Hirst, Jennifer1, Author
Itzhak, Daniel N.2, Author              
Antrobus, Robin1, Author
Borner, Georg H. H.2, Author              
Robinson, Margaret S.1, Author
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1external, ou_persistent22              
2Borner, Georg / Systems Biology of Membrane Trafficking, Max Planck Institute of Biochemistry, Max Planck Society, ou_3060205              

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Free keywords: SPASTIC PARAPLEGIA; MEMBRANE-PROTEINS; CELL-SURFACE; IDENTIFICATION; TRAFFICKING; RETROMER; DISEASE; QUANTIFICATION; LYSOSOMES; MUTATIONSBiochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics;
 Abstract: The AP-5 adaptor protein complex is presumed to function in membrane traffic, but so far nothing is known about its pathway or its cargo. We have used CRISPR-Cas9 to knock out the AP-5. subunit gene, AP5Z1, in HeLa cells, and then analysed the phenotype by subcellular fractionation profiling and quantitative mass spectrometry. The retromer complex had an altered steady-state distribution in the knockout cells, and several Golgi proteins, including GOLIM4 and GOLM1, were depleted from vesicle-enriched fractions. Immunolocalisation showed that loss of AP-5 led to impaired retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR), GOLIM4, and GOLM1 from endosomes back to the Golgi region. Knocking down the retromer complex exacerbated this phenotype. Both the CIMPR and sortilin interacted with the AP-5 +/- associated protein SPG15 in pull-down assays, and we propose that sortilin may act as a link between Golgi proteins and the AP-5/SPG11/SPG15 complex. Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. This provides a mechanistic explanation for why mutations in AP-5/SPG11/SPG15 cause cells to accumulate aberrant endolysosomes, and highlights the role of endosome/lysosome dysfunction in the pathology of hereditary spastic paraplegia and other neurodegenerative disorders.

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Language(s): eng - English
 Dates: 2018-01-30
 Publication Status: Published online
 Pages: 28
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 Table of Contents: -
 Rev. Type: Peer
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Title: PLoS Biology
  Other : PLoS Biol.
Source Genre: Journal
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Publ. Info: Public Library of Science
Pages: - Volume / Issue: 16 (1) Sequence Number: e2004411 Start / End Page: - Identifier: ISSN: 1544-9173
CoNE: https://pure.mpg.de/cone/journals/resource/111056649444170