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

Nag, Sudeshna and Rani, Shikha and Mahanty, Sarmistha and Bissig, Christin and Arora, Pooja and Azevedo, Cristina and Saiardi, Adolfo and van der Sluijs, Peter and Delevoye, Cedric and van Niel, Guillaume and Raposo, Graca and Setty, Subba Rao Gangi (2018) Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles. In: JOURNAL OF CELL SCIENCE, 131 (18).

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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 orRabip4/4' (isoforms encoded by Rufy1) and differentially regulate cargo sorting from SEs. Thus, Rab4A acts a key regulator of cargo segregation on SEs. This article has an associated First Person interview with the first author of the paper.

Item Type:	Journal Article
Publication:	JOURNAL OF CELL SCIENCE
Publisher:	COMPANY BIOLOGISTS LTD
Additional Information:	Copy right for this article belong to Copy right for this article belong to
Keywords:	Rab4A; AP-3; KIF3; Rabenosyn-5; Rabaptin-5; Rabip4'; Sorting endosome; Melanosome biogenesis
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	15 Nov 2018 14:11
Last Modified:	15 Nov 2018 14:11
URI:	http://eprints.iisc.ac.in/id/eprint/61075

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