Journal of Cell Science nvriyo abig,CmrdeIsiuefrMdclRsac,adDprmn fCiia iceity debok’ optl il Road, Hills Hospital, Addenbrooke’s Biochemistry, Clinical of Department and Research, Medical for Institute Cambridge Cambridge, of University Seaman J. N. Matthew recycling protein beyond endosomal and – complex retromer The Commentary h ermrcmlxwsfrtietfe nteyeast the in identified first was complex cerevisiae Saccharomyces retromer The retromer of identification The the into sorting. insights protein understanding new endosomal generated in of have advances mechanisms retromer will of the retromer-mediated biology I how of cell discuss the Commentary, studies for and this from sorting cargo protein In findings its proteins. recent efficient mediating summarise endosomal partitions thereby of then tubule, nascent retrieval and a into recognises and incorporation retromer development how metazoan (AD). of disease Alzheimer the as aspects such proteins, as pathologies such membrane processes biogenesis, to linked amyloid many been lysosome has binds of complex retromer the localisation that 2012). of al., activity the protein et Fjorback mediating a 2007; al., By SorLA), et (Nielsen (APP) as protein precursor known (sortilin-related also SorL1 and 2011), polarity, receptor, cell al., for et required protein (Pocha protein apical (Crb) transport an transporter Crumbs Wnt 2008), iron the (Eaton, receptor the 2010), Wntless/MIG-14 al., 2004), 6-phosphate et al., (Tabuchi et mannose DMT1-II/Slc11a2 Arighi 2004; independent cargo (Seaman, cation transport cargoes (CIMPR) retromer that the Prominent destination. form include: the appropriate of the tubules regions to discrete where proteins into concentrated membrane are membrane that endosomal specific – recognising cargo – protein by endosomal proteins operates the and of component machinery key sorting a is complex retromer The Introduction processes. physiological mechanisms of set of the understanding diverse the and a in to paraplegia advances contributes recent words: spastic highlight retromer Key will how and I to discuss Commentary, disease leads and this Alzheimer sorting In sorting understood. protein protein as be set endosomal endosomal to complex such retromer-mediated retromer-mediated starting a are of of diseases pathologies centre Dysregulation the these neurodegenerative sorting. at underlying signalling including squarely protein protein retromer of endosomal endosomal pathologies, place regulation how governs and show and various microtubules, that now along the sorting machinery complexes movement membrane including protein protein and endosome-to-plasma macromolecular assembly endosome-to-Golgi proteins, of other actin of the with retromer-interacting and aspects beyond coordinated complex retromer for new is retromer of required sorting the identified role is between the have interactions extends retromer The now retromer that which events. of revealed receptors protein, hydrolase has Wntless/MIG-14 studies is of the and Retromer pool in as pathway active eukaryotes. such progress an all cargo maintain across and Recent to conserved complex necessary is network. WASH is that trans-Golgi and machinery pathway sorting the retrieval protein endosome-to-Golgi in endosomal the the with of associated element closely vital most a is complex retromer The Summary 10.1242/jcs.103440 doi: 4693–4702 125, ß Science Cell of Journal [email protected] UK 0XY, CB2 Cambridge 02 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2012. hr a eetybe infcn rgesi determining in progress significant been recently has There ermr nooe eyln,Srig AHcomplex WASH Sorting, Recycling, Endosome, Retromer, n a hw omdaeendosome- mediate to shown was and e ifrnei ht nmmaincls ermri o a not is retromer cells, mammalian in that, eukaryotes. is higher difference in key retromer A and yeast in retromer prototypical 2007). specifically al., For orthologue, et Vps17p (Wassmer Vps17p. Snx6 a or with of Snx5 namely dimerise either Vps5p, orthologue Snx2 of or homologues an the Vps5- Snx1 cells a with mammalian whereby in associates dimer, example, a protein is to component similar like addition, Snx-BAR In the complex. yeast, yeast in the is higher protein trimer to in selective identical cargo endosomal and the essentially cells, conserved, mammalian in as highly such family functions are eukaryotes, subunits retromer Snx Retromer how sorting. the about to of learned proteins members 2010). Snx-BAR Cullen, other and as Attar from in (reviewed described them frequently related distinguish and Vps17p are Vps5p, 2004). 1997; al., et proteins al., Peter et 2001; al., Horazdovsky et 1997; Kurten Hindes, and self-assembly to (Nothwehr intrinsic activity an believed and Bin- are C-terminal domains and their (BAR) through Amphiphysin-Rvs family formation vesicle (Snx) or are nexin tubule proteins mediate sorting Vps17 and the Vps5 of of The Vps17p. members with trimer Vps5p of a and dimer yeast selection, cargo a subcomplexes: mediates The which and Vps26p, two 1998). and Vps29p biochemically Vps35p, al., into be et dissected ( can Seaman phenotypically sorting complex 1997; protein retromer al., vacuole heteropentameric by et encoded five (Seaman receptor comprises all genes (CPY) yeast, are in Y that characterised peptidase proteins as carboxy complex, The the Vps10p. of retrieval to-Golgi hr r,hwvr motn ifrne ewe the between differences important however, are, There been has much identified, was retromer since years 14 the In 4693 VPS ) Journal of Cell Science otlnpoen nw ag o ermr(emn 2004; (Seaman, retromer a the for disease, to cargo Batten bind to known in shown a mutated been protein, has is and sortilin CLN5 Rab7a disorder, 2012). through storage of lysosomal complex al., regulation cargo-selective the et the to (Mamo of protein recruitment (CLN5) the 5 neuronal lipofuscinosis amoeba enteric through from 2005). studies conserved al., in et is reported (Nakada-Tsukui first Rab7a was and and between evolution complex trimer association The cargo-selective cargo-selective 2009). al., GTPase the et the small Seaman of 2008; the recruitment al., that et for (Rojas shown required been is now Rab7a has lipid- It known a domain. proteins contain for binding the complex necessary of cargo-selective none the is dimer, comprise that Snx-BAR recruitment the its Unlike selection. because is cargo membrane question the to important recruited an is complex cargo-selective the complex How cargo-selective the of Recruitment PtdIns(3) of Production 2002). Snx al., each in et through present is (Cozier mediated which domain, protein (PX) is homology Phox dimer the [PtdIns(3) by Snx-BAR 3-phosphate (PtdIns) phosphatidylinositol the to binding of recruitment dimer The Snx of the of key Recruitment Recruitment a function. therefore occur. retromer of is can regulation endosome that the the sorting of the so to element cargo subcomplexes membrane formation, retromer the of tubule the from rounds Following dissociate to further then sorted. proteins assembles which are into retromer dimer tubules proteins membrane Snx-BAR cargo endosomal of the formation promote Vps35–Vps29–Vps26 Simultaneously, the by endosomal mediated trimer. process the a of selection – to the proteins with cargo subcomplexes concomitantly occurs or retromer precedes membrane the of membrane the Recruitment to retromer this of Recruitment of implications the yeast; below. discussed in are conserved observation not higher the in are studies or from eukaryotes identified proteins many trimer accessory of that retromer cargo-selective apparent the unit also of the is functional It to, dimer. which higher Snx-BAR referred that membrane-bending specify other being means to or is difference important retromer cells This is mammalian 2010). it in al., eukaryotes, retromer et discussing (Nisar Prosser other when including 2010; the retromer of al., the systems function et of the of one requiring reports only model without of utilise subcomplexes that number various processes growing and a proteins now in cargo are there al., studies cells, et mammalian Snx (Swarbrick From Snx6) the or Snx5 and 2011). with Vps29) Snx2 or and (Snx1 Vps26 components (Vps35, the of trimer association transient cargo-selective more much a but heteropentamer stable 4694 ebaeidpnetyo h ag-eetv complex cargo-selective the 2004). 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al., genes be et that underlying al., Wen 2010; recently et could al., the shown et (Small Lane increases although expression 2008; unknown al., et presently tissue, function retromer is from neuronal that retromer cause tissue underlying in of indicates of studies downregulated the patients and Loss APP, to AD of AD. processing contributes amyloidogenic of sorting to retromer-mediated that retromer pathology 2007; protein suggests for al., strongly 2005; et 2012) requirement endosomal (Nielsen al., al., the SorL1/SorLA et et the of and Fjorback localisation (Andersen mediating 2006) the APP in al., regulate of has et processing SorL1/SorLA Andersen and that role localisation prominent The disease and Retromer al., displacing et for Collins responsible is is 2006; Vps26 subunit the al., b that Vps26 et likely the seems (Shi it in As arrestins 2008), retromer 2). to for (Fig. similar role event structurally direct signalling a a revealing regulating cAMP, of production of the displacement the is It surface. thereby PTHR, with associates displacing complex retromer the the reaches its complex endosome, PTHR-arrestin through the cyclic Once endocytosed pits. initiates clathrin-coated then PTHR is with receptor, and interaction production the (cAMP) of AMP activation ligand Upon and 2011). al., binding et (Feinstein signalling receptor regulates arsi rmPTHR. from -arrestin n ae frglto frtoe–ag neatoscould interactions retromer–cargo of regulation of layer One nadto oarl o ermrfnto nA pathogenesis, AD in function retromer for role a to addition In b arsi omdaetertivlo TRt h cell the to PTHR of retrieval the mediate to -arrestin b -deegcrcpo Tmi ta. 01,and 2011), al., et (Temkin receptor 2-adrenergic b arsi n usqeticroaininto incorporation subsequent and -arrestin htsnwwt ermr4699 retromer with new What’s b arsi yrtoe htstops that retromer by -arrestin Snx3 and Rab7a Journal of Cell Science eg h tupli uui fteWS ope)rslsin results complex) thus WASH retromer the retromer APP, of of with subunit operate of Mutation strumpellin that the proteins AD. processing (e.g. or in in Vps35) role (e.g. and function components key transport. a retromer localisation has membrane implicating and the endosome-to-plasma signalling GPCR in mediating regulate role can a Retromer complex, WASH through has the as and, also such proteins retrieval accessory with endosome-to-Golgi interactions mediates Retromer perspectives future avenue and interesting Conclusions an retrieval be might retromer-mediated but explore. determined, of to be occurs downregulation to CIMPR and remains Atg9 the of localisation autophagy. the through of to in induction shift firstly The upon this reduced 2006). localising Whether also al., is it et CIMPR of (Young in retrieval autophagosomes however, resulting then autophagy reduced, and endosomes of is normal induction recycling Under Upon the Atg9 autophagy. between endosomes. cycles and for Atg9 Golgi protein required autophagosome directly the conditions, more be also TBC1D5 by autophagy. Rab7a in of checkpoint activity a the of provide regulation might of the fusion 2004), the TBC1D5 al., (Ja for et that required lysosomes A speculate is with Rab7a to 2011). to autophagosomes As tempting yet activity. al., has is Rab7a autophagy it et regulates in through although TBC1D5 Orvedahl mitochondria of reported, role 2012; and be of the of clearance al., LC3, analysis the et detailed protein – (Popovic marker mitophagy autophagy in autophagy have might role it the that been a indicated to have recently screens has siRNA-based bind retromer-associated that functional TBC1D5 to system. expected of processes endocytic shown be physiological the function additional to involve to the that therefore contribute is might and It proteins function established. retromer well sorting protein now endosomal in retromer is of importance and role The sorting Fam21 protein the 2008). endosomal require Beyond al., et to (Huang shown complex to and been WASH 2011), the bind has al., of virus et subunit can 2010). CIMPR Vaccinia (Kingston reduced virus of CD4 al., to of entry Herpes leading et downregulation function, and of (Braun retromer levels protein inhibit has proteins to Tip Snx3 Vps35 Snx3 retromer role the 2007). this Salmonella-containing with in Additionally, whether of al., associated clear yet maturation et not is is of the (Bujny it although transport in endosomes, toxin example, endosome-to-Golgi implicated Shiga For the been pathogens. bacterial for of required number the a is by retromer hijacked is function this of effect (Zimprich Vilarin determined 2011; precise be al., to the et yet has although function retromer disease, on inherited mutation an Parkinson in causal of be to shown form been has A Vps35 disease. of neurodegenerative mutation of rare mutations forms point other that for evidence responsible is be there 1992), can al., et Lee 1991; al., et ope uuisaeepce ob ehl shsbe shown been has retromer as lethal, of be to mutations for expected are loss-of-function subunits complex complete 2011). al., is et (Ropers Although KIAA1033/SWIP disability intellectual hereditary subunit a in complex mutated WASH the Furthermore, 4700 h nooet-og erea ucino ermrmight retromer of function retrieval endosome-to-Golgi The retromer disease, neurodegenerative in role a with Along Vps26a ora fCl cec 2 (20) 125 Science Cell of Journal ntasei ncoteprmnsi ie(Radice mice in experiments knockout transgenic in ˜o-Gu ele l,2011). al., et ¨ell gre l,20;Gutierrez 2004; al., et ¨ger ud,P,Pdla .M,Sra,S n m,S D. S. Emr, and S. Sarkar, J. M., S. P. Padilla, Cullen, P., and Burda, L. Johannes, V., D. Popoff, R. Teasdale, V., and M. M. B. Bujny, Collins, J., Griffin, C., M. Kerr, Y., Zhe, A., Bugarcic, rat .M,Kr,M . amn,L . oeh .R,Mso,K E., K. Mostov, R., S. Joseph, A., L. Hammond, C., M. Kerr, M., D. Bryant, ru,V,Wn,A,Lnei,M,Hn,W . rnti,S n rml,J H. J. Brumell, and S. Grinstein, J., W. Hong, M., Landekic, A., Wong, V., Braun, onr .H,Atou,R,Hrt . hmr,G . oi,P,Jcsn .P., L. Jackson, P., Kozik, S., G. Bhumbra, S. J., M. Hirst, Robinson, R., and Antrobus, S. H., K. G. Lilley, Borner, S., Hester, M., Harbour, H., E. G. Reid, Borner, and D., J. Yan, C. V., O’Kane, Y. C., Sharma, L., Blackstone, Cheng, B., Zhou, X., Tang, Y., Wu, Y., T. Belenkaya, ta,N n uln .J. P. Cullen, and N. Attar, rgi .N,Hrnl,L . gia,R . at .R n oiaio .S. J. Bonifacino, and R. C. Haft, C., R. Aguilar, M., L. Hartnell, N., C. Arighi, nesn .M,Shit . pegn . lean . ele . aai,D., Galatis, J., Behlke, J., Gliemann, R., Spoelgen, V., Schmidt, M., O. Andersen, ecie,btissoyhsol utbegun. first just was only retromer has since story years its 14 but is described, It might retromer. regulating modifications role in post-translational what play other unknown be (see currently or Fam21 can is phosphorylation and it proteins dimer but retromer-associated http://www.uniprot.org/), Snx-BAR the or including of proteins phosphorylated, Several that post- retromer phosphorylation. events through as the future possibly signalling such function, modifications that identify to translational retromer various likely will regulate on response and impinges is themselves activity in pathways it retromer how signalling at initiated processed, reveal operates will are signals research retromer stimuli many that extracellular regulating where Given in roles sorting. interesting endosomes, have protein will endosomal that discovered be will be proteins will retromer-associated also additional disease, I that localisation. anticipate appropriate in their would for implicated correct retromer require proteins that their identified membrane for or retromer important proteins physiologically possibly that on proteins, likely membrane seems depend additional it and month-by-month that increasing is proteins localisation cargo of HSP. including and disease, disease neurodegenerative Parkinson progressive of forms other nesn .M,Rih,J,Shit . otad,M,Sole,R,Bhk,J., Behlke, R., Spoelgen, M., Gotthardt, V., Schmidt, J., Reiche, M., O. Andersen, References UK the G0701444]. from number award [grant Fellowship Council Senior Research a Medical through funded is M.N.J.S. Funding manuscript. the Caroline on and Breusegem comments Sophie helpful colleagues for my Freeman thank to like would I Acknowledgements nooet-og ergaetasoti euae yteyatVs4Pdn 3- PtdIns Vps34 yeast the by regulated is kinase. transport retrograde endosome-to-Golgi complexes. retromer distinct define 1759-1773. subunits Vps26B and Vps26A (2011). rmeryedsm otetasGlinetwork. Golgi toxin trans Shiga the of to transport retrograde endosome efficient early for from required is nexin-1 sorting component E-cadherin. L. of J. recycling Stow, modulated and D. R. Teasdale, nue ySloel n novdi auaino h Salmonella-containing network the endosomal of tubular maturation a in of component involved a and is vacuole. 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