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Journal Article

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

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Itzhak,  Daniel N.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Borner,  Georg H. H.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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journal.pbio.2004411.pdf
(Publisher version), 17MB

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5836260.zip
(Supplementary material), 4MB

Citation

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.


Cite as: https://hdl.handle.net/21.11116/0000-0000-B177-2
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.