The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics

Abstract

Research Article 3703 IntroductionEndosomal protein sorting has a vital role in a number of physiologically important processes including antigen presentation, macromolecular nutrient uptake, growth factor receptor signaling and downregulation, autophagy and lysosome biogenesis (for reviews, see Sadowski et al., 2009;Saksena and Emr, 2009;Sann et al., 2009;Seaman, 2008;Lee et al., 2008). Recent studies of inherited diseases have identified several examples of genes encoding proteins that function in endosomal protein sorting that, when mutated, result in a range of pathologies. A notable example is hereditary spastic paraplegias (HSP), the hallmark of which is a selective distal axonopathy. There is a striking localisation of many of the HSP-encoded proteins to the endosome, including the microtubule-severing protein spastin, the ubiquitin-ligase-interacting protein spartin, and NIPA1, a membrane protein that mediates bone morphogenic protein signaling at the endosome (Tsang et al., 2009; for a review, see Salinas et al., 2008). Despite this concentration of HSP proteins at endosomes, in most cases their function is unknown.Much of the core machinery that carries out endosomal protein sorting is conserved in evolution, for example, the retromer complex (for reviews, see Attar and Cullen, 2009;Verges, 2008;Collins, 2008;Bonifacino and Hurley, 2008). Retromer mediates endosometo-Golgi retrieval of lysosomal and vacuolar hydrolase receptors (e.g. the cation-independent mannose 6 phosphate receptor, CIMPR) along with other physiologically significant membrane proteins including wntless, which functions in WNT secretion, and SORL1, a protein that is genetically linked to late-onset Alzheimer's disease (Arighi et al., 2004;Seaman, 2004;Eaton, 2008;Nielsen et al., 2007;Rogaeva et al., 2007).The retromer complex was first identified in yeast where it comprises five proteins encoded by vacuolar protein sorting (VPS) genes. The heteropentameric retromer complex can be functionally dissected into two subcomplexes: a cargo-selective complex formed from a conserved trimer of Vps35p, Vps29p and Vps26p and a 'structural complex' formed from a dimer of the sorting nexin (SNX) proteins Vps5p and Vps17p (Seaman et al., 1998). In mammals, SNX1, SNX2 with SNX5 and SNX6 provide the 'structural' role and can tubulate membranes through the C-terminal Bin, amphiphysin and Rvs (BAR) domains present in these proteins (Carlton et al., 2004;Wassmer et al., 2007). Additionally, SNX5 and SNX6 interact with the microtubule cytoskeleton via the p150glued protein that binds to dynein, thereby linking endosomal protein sorting to microtubules (Wassmer et al., 2009;Hong et al., 2009).The interaction between the SNX component of retromer and p150glued is an example of how retromer-interacting proteins facilitate retromer in mediating endosome-to-Golgi retrieval. In yeast, the SNX3 homologue Grd19p binds to Ftr1p to sort Ftr1p into the retromer pathway (Strochlic et al., 2008). In mammalian cells, the EPS15 homology domain protein, EHD1, interacts ...

Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome

“…17 WASHdependent actin polymerization promotes scission of transport intermediates of the different endosomal routes and affects recycling, 17 degradation, 18 and retrograde pathways. 19,20 Inactivating variants in the gene encoding the WASH subunit strumpellin has been recently shown to cause a form of RSS/3C syndrome. 2 Variant in another component of the WASH complex, SWIP, was shown to be causal to non-syndromic ID.…”

Nuclear localized FAM21 participates in NF-κB-dependent gene regulation in pancreatic cancer cells

“…In fact, previous studies have shown that the LFa motifs within the FAM21 tail directly interact with VPS35 (Gomez and Billadeau, 2009;Harbour et al, 2010;Jia et al, 2012) promoting endosomal accumulation and the regulation of endosome to plasma membrane as well as retrograde endosome to Golgi trafficking. Importantly, our results suggest that recruitment by the retromer is required for normal FAM21 nuclear accumulation (Fig.…”

“…FAM21-VPS35 interaction is necessary for recruitment of WASH complex to endosomal membranes (Gomez and Billadeau, 2009;Harbour et al, 2010;Harbour et al, 2012;Helfer et al, 2013). Notably, a rare autosomal-dominant VPS35 mutation (D620N) has recently been identified as a cause of Parkinson's disease owing to destabilized retromer-WASH complex association and impaired autophagy (McGough et al, 2014;Zavodszky et al, 2014).…”

Evolutionary variations of VPS29, and their implications for the heteropentameric model of retromer

“…Another important difference between retromer in S. cerevisiae and mammals is that mammalian retromer associates with a number of accessory proteins including the WASH complex and a RAB GTPase activating protein (GAP), TBC1D5. 6 The difference between retromer in S. cerevisiae and higher eukaryotes is intriguing but also important for understanding the molecular mechanisms of retromer-mediated endosomal protein sorting.…”