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Journal of cell science
09 20, 2018;131 (18):

Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles.

Sudeshna Nag, Shikha Rani, Sarmistha Mahanty, Christin Bissig, Pooja Arora, Cristina Azevedo, Adolfo Saiardi, Peter van der Sluijs, Cedric Delevoye, Guillaume van Niel, Graca Raposo, Subba Rao Gangi Setty
Author Information
  1. Sudeshna Nag: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012. ORCID
  2. Shikha Rani: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012. ORCID
  3. Sarmistha Mahanty: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012.
  4. Christin Bissig: Institut Curie, PSL Research University, CNRS, UMR 144, Structure and Membrane Compartments, F-75005, Paris, France.
  5. Pooja Arora: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012. ORCID
  6. Cristina Azevedo: Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
  7. Adolfo Saiardi: Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
  8. Peter van der Sluijs: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands.
  9. Cedric Delevoye: Institut Curie, PSL Research University, CNRS, UMR 144, Structure and Membrane Compartments, F-75005, Paris, France.
  10. Guillaume van Niel: Institut Curie, PSL Research University, CNRS, UMR 144, Structure and Membrane Compartments, F-75005, Paris, France.
  11. Graca Raposo: Institut Curie, PSL Research University, CNRS, UMR 144, Structure and Membrane Compartments, F-75005, Paris, France.
  12. Subba Rao Gangi Setty: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012 subba@iisc.ac.in. ORCID
PMID: 30154210 DOI: 10.1242/jcs.216226

Abstract

Sorting endosomes (SEs) are the regulatory hubs for sorting cargo to multiple organelles, including lysosome-related organelles, such as melanosomes in melanocytes. In parallel, melanosome biogenesis is initiated from SEs with the processing and sequential transport of melanocyte-specific proteins toward maturing melanosomes. However, the mechanism of cargo segregation on SEs is largely unknown. Here, RNAi screening in melanocytes revealed that knockdown of Rab4A results in defective melanosome maturation. Rab4A-depletion increases the number of vacuolar endosomes and disturbs the cargo sorting, which in turn lead to the mislocalization of melanosomal proteins to lysosomes, cell surface and exosomes. Rab4A localizes to the SEs and forms an endosomal complex with the adaptor AP-3, the effector rabenosyn-5 and the motor KIF3, which possibly coordinates cargo segregation on SEs. Consistent with this, inactivation of rabenosyn-5, KIF3A or KIF3B phenocopied the defects observed in Rab4A-knockdown melanocytes. Further, rabenosyn-5 was found to associate with rabaptin-5 or Rabip4/4' (isoforms encoded by ) and differentially regulate cargo sorting from SEs. Thus, Rab4A acts a key regulator of cargo segregation on SEs.This article has an associated First Person interview with the first author of the paper.

Keywords

AP-3 KIF3 Melanosome biogenesis Rab4A Rabaptin-5 Rabenosyn-5 Rabip4′ Sorting endosome

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Grants

  1. 500122-Z-09-Z/DBT-Wellcome Trust India Alliance
  2. MC_U122680443/Medical Research Council
  3. MC_UU_00012/4/Medical Research Council
  4. MC_UU_12018/4/Medical Research Council

MeSH Term

Endosomes
Humans
Lysosomes
rab4 GTP-Binding Proteins

Chemicals

rab4 GTP-Binding Proteins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

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