Retromer is required for the retrograde sorting of cation-independent mannose 6-phophate receptor into a subset of endosome transport carriers

Cui Y1, Carosi J2,3, Yang Z1, Kerr M4, Sargeant T2,5 and Teasdale R1

  1. School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
  2. Hopwood Centre for Neurobiology, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  3. Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
  4. Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
  5. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.

Retromer is a peripheral protein complex that coordinates multiple vesicular trafficking events within the endo-lysosomal system. Here, we demonstrate that retromer is required for the maintenance of normal lysosomal function. At the whole cell level, the knockout of retromer Vps35 subunit reduces the lysosomal proteolytic capacity, as a consequence of the improper processing of lysosomal hydrolases, dependent on the cation-independent mannose 6-phophate receptor (CI-M6PR) trafficking. Moreover, we identify that CI-M6PR, sorted via the retromer-dependent process, is incorporated into a subset of endosome transport carriers (ETCs) tethered by a specific trans-Golgi protein. Finally, we show that this retromer-dependent retrograde cargo trafficking pathway also requires a specific retromer-associated endosomal protein.