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

Journal of Cell Science
Sudeshna NagSubba Rao Gangi Setty

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 Rufy1) and differentially regulate cargo sorting from SEs. Thus, Rab4A acts a key regulator of cargo segregation on SEs.This article ...Continue Reading

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Nov 21, 2018·Expert Review of Proteomics·Bethany ClaridgeDavid W Greening
Aug 28, 2020·Frontiers in Cell and Developmental Biology·Rémy Char, Philippe Pierre
Aug 28, 2020·Frontiers in Cell and Developmental Biology·Gregory M I RedpathJérémie Rossy
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Feb 6, 2020·Molecular Cancer Research : MCR·Kate TubbesingMargarida Barroso
May 23, 2021·Integrative and Comparative Biology·Linh LeMichael S Marks

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Methods Mentioned

BETA
GTPases
gene knockdown
transfection
PMEL
Electron microscopy
immunoprecipitation
co-IP
GTPase
two-hybrid
fluorescence-activated cell sorting

Software Mentioned

Image Lab
ImageJ
GraphPad
cellSens Dimension
FlowJo Tree Star
Zen lite

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