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Endosomal recruitment of the WASH complex: active sequences and mutations impairing interaction with the retromer.

Abstract：

BACKGROUND INFORMATION:The Wiskott-Aldrich syndrome protein and scar homolog (WASH) complex is the major Arp2/3 activator at the surface of endosomes. The branched actin network, that the WASH complex induces, contributes to cargo sorting and scission of transport intermediates destined for most endosomal routes. A major challenge is to understand how the WASH molecular machine is recruited to the surface of endosomes. The retromer endosomal machinery has been proposed by us and others to play a role in this process. RESULTS:In this work, we used an unbiased approach to identify the endosomal receptor of the WASH complex. We have delineated a short fragment of the FAM21 subunit that is able to displace the endogenous WASH complex from endosomes. Using a proteomic approach, we have identified the retromer cargo selective complex (CSC) as a partner of the active FAM21 sequence displacing the endogenous WASH complex. A point mutation in FAM21 that abolishes CSC interaction also impairs WASH complex displacement activity. The CSC is composed of three subunits, VPS35, VPS29 and VPS26. FAM21 directly binds the VPS35 subunit of the retromer CSC. Additionally, we show that a point mutant of VPS35 that blocks binding to VPS29 also prevents association with FAM21 and the WASH complex revealing a novel role for the VPS35-VPS29 interaction in regulating retromer association with the WASH complex. CONCLUSIONS:This novel approach of endogenous WASH displacement confirms previous suggestions that the retromer is the receptor of the WASH complex at the surface of endosomes and identify key residues that mediate this interaction. The interaction between these two endosomal machineries, the WASH complex and the retromer, is likely to play a critical role in forming platforms at the surface of endosomes for efficient sorting of cargoes.

journal_name

Biol Cell

journal_title

Biology of the cell

authors

Helfer E,Harbour ME,Henriot V,Lakisic G,Sousa-Blin C,Volceanov L,Seaman MNJ,Gautreau A

doi

10.1111/boc.201200038

subject

Has Abstract

pub_date

2013-05-01 00:00:00

pages

191-207

issue

eissn

0248-4900

issn

1768-322X

journal_volume

105

pub_type

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Endosomal recruitment of the WASH complex: active sequences and mutations impairing interaction with the retromer.