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Retromer has a selective function in cargo sorting via endosome transport carriers

Cui, Yi, Carosi, Julian M., Yang, Zhe, Ariotti, Nicholas, Kerr, Markus C., Parton, Robert G., Sargeant, Timothy J., Teasdale, Rohan D.·2019·Journal of Cell Biology

Abstract

Retromer is a peripheral membrane protein complex that coordinates multiple vesicular trafficking events within the endolysosomal system. Here, we demonstrate that retromer is required for the maintenance of normal lysosomal morphology and function. The knockout of retromer subunit Vps35 causes an ultrastructural alteration in lysosomal structure and aberrant lysosome function, leading to impaired autophagy. At the whole-cell level, knockout of retromer Vps35 subunit reduces lysosomal proteolytic capacity as a consequence of the improper processing of lysosomal hydrolases, which is dependent on the trafficking of the cation-independent mannose 6-phosphate receptor (CI-M6PR). Incorporation of CI-M6PR into endosome transport carriers via a retromer-dependent process is restricted to those tethered by GCC88 but not golgin-97 or golgin-245. Finally, we show that this retromer-dependent retrograde cargo trafficking pathway requires SNX3, but not other retromer-associated cargo binding proteins, such as SNX27 or SNX-BAR proteins. Therefore, retromer does contribute to the retrograde trafficking of CI-M6PR required for maturation of lysosomal hydrolases and lysosomal function.

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  • Loss of retromer leads to impaired mTORC1 activity, induction of autophagy, and the appearance of swollen and evenly dispersed lysosomes.

    “This leads to impaired mTORC1 activity and the induction of autophagy, and the appearance of swollen and evenly dispersed lysosomes (Jimenez-Orgaz et al., 2018; Cui et al., 2019; Curnock et al., 2019; Kvainickas et al., 2019).”

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Metadata

Authors
Cui, Y., Carosi, J. M., Yang, Z., Ariotti, N., Kerr, M. C., Parton, R. G., Sargeant, T. J., & Teasdale, R. D.
Affiliations
  • School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia 1
  • Hopwood Centre for Neurobiology, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia 2
  • Institute for Molecular Biosciences and Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland, Australia 4
Venue
Journal of Cell Biology
Published
2018-12-17
Volume
218
Issue
2
Pages
615-631
ISSN
  • 0021-9525
  • 1540-8140
Cited by
152
References
0
Language
en
Funders
  • Australian Research Council (DP160101573)
  • National Health and Medical Research Council (APP1037320, APP1058565, APP569542, APP1045092, APP1041929)
  • China Scholarship Council

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