title: RME-8 coordinates the activity of the WASH complex with the function of the retromer SNX dimer to control endosomal tubulation.
abstract: Retromer is a vital element of the endosomal protein sorting machinery and comprises two subcomplexes that operate together to sort membrane proteins (cargo) and tubulate membranes. Tubules are formed by a dimer of sorting nexins, a key component of which is SNX1. Cargo selection is mediated by the VPS35-VPS29-VPS26 trimer, which additionally recruits the WASH complex through VPS35 binding to the WASH complex subunit FAM21. Loss of function of the WASH complex leads to dysregulation of endosome tubulation, although it is unclear how this occurs. Here, we show that FAM21 also binds to the SNX1-interacting DNAJ protein RME-8. Loss of RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly branched endosomal tubules. Building on previous observations from other laboratories, we show that these tubules contain membrane proteins that are dependent upon WASH complex activity for their localization to the plasma membrane. Therefore, we propose that the interaction between RME-8 and the WASH complex provides a means to coordinate the activity of the WASH complex with the membrane-tubulating function of the sorting nexins at sites where retromer-mediated endosomal protein sorting occurs.
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research/Department of Clinical Biochemistry, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Freeman
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hesketh
authors.forename: Matthew N J
authors.initials: MN
authors.lastname: Seaman
mesh_terms: D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*
chemical_list: C507525:DNAJC13 protein, human; D008840:Microfilament Proteins; D018832:Molecular Chaperones; C549919:WASH protein, human
keywords: Endosome tubule; RME-8; Retromer; SNX; WASH complex