RME-8 coordinates the WASH complex with the retromer SNX-BAR dimer to control endosomal tubulation

Abstract

Retromer is a vital element of the endosomal protein sorting machinery, and comprises two sub-complexes that operate together to sort membrane proteins (cargo) and tubulate membranes. Tubules are formed by the sorting nexin dimer, a key component of which is SNX1. Cargo selection is mediated by the VPS35-VPS29-VPS26 trimer, which additionally recruits the WASH complex via VPS35 binding to the WASH complex subunit FAM21. Loss of WASH complex function leads to dysregulation of endosome tubulation, although it is not clear 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. Extending the observations of Popoff et al. (2009), we show that these contain membrane proteins dependent on WASH complex activity for localization to the plasma membrane. We therefore propose that the RME-8/WASH complex interaction provides a potential 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.