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

Journal of Cell Science, Nov 2010

Michael E. Harbour, Sophia Y. A. Breusegem, Robin Antrobus, Caroline Freeman, Evan Reid, Matthew N. J. Seaman

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

Michael E. Harbour 1 Sophia Y. A. Breusegem 1 Robin Antrobus Caroline Freeman 0 Evan Reid 0 Matthew N. J. Seaman 1 0 Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrookes Hospital , Cambridge CB2 0XY , UK 1 Department of Clinical Biochemistry Summary The retromer complex is required for the efficient endosome-to-Golgi retrieval of the CIMPR, sortilin, SORL1, wntless and other physiologically important membrane proteins. Retromer comprises two protein complexes that act together in endosome-to-Golgi retrieval; the cargo-selective complex is a trimer of VPS35, VPS29 and VPS26 that sorts cargo into tubules for retrieval to the Golgi. Tubules are produced by the oligomerization of sorting nexin dimers. Here, we report the identification of five endosomally-localised proteins that modulate tubule formation and are recruited to the membrane via interactions with the cargo-selective retromer complex. One of the retromer-interacting proteins, strumpellin, is mutated in hereditary spastic paraplegia, a progressive length-dependent ce axonopathy. Here, we show that strumpellin regulates endosomal tubules as part of a protein complex with three other proteins that n include WASH1, an actin-nucleating promoting factor. Therefore, in addition to a direct role in endosome-to-Golgi retrieval, the cargoe ic selective retromer complex also acts as a platform for recruiting physiologically important proteins to endosomal membranes that S regulate membrane tubule dynamics. - l l e C Key words: Retromer, Endosome, Tubule, Recruitment, Strumpellin f o l a run IEnntdroosodmuacltiporontein sorting has a vital role in a number of Jo 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 Alzheimers 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 with retromer and is required to stabilize SNX1-positive membrane tubules (Gokool et al., 2007a). Recruitment of the cargo-selective retromer complex to the endosomal membrane is mediated by the small GTPase RAB7 (Rojas et al., 2008; Seaman et al., 2009). Additionally, the cargo-se (...truncated)


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Michael E. Harbour, Sophia Y. A. Breusegem, Robin Antrobus, Caroline Freeman, Evan Reid, Matthew N. J. Seaman. The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics, Journal of Cell Science, 2010, pp. 3703-3717, 123/21, DOI: 10.1242/jcs.071472