Bidirectional Transport Between the Trans-Golgi Network and the Endosomal System

Molecular Membrane Biology, 2010; Early Online, 1–14

Bidirectional transport between the trans-Golgi network and the endosomal system

MIHAELA ANITEI1*, THOMAS WASSMER1,2*, CHRISTOPH STANGE1 & BERNARD HOFLACK 1

1Biotechnology Center, Dresden University of Technology, Tatzberg, Dresden, Germany, and 2School of Life and Health Sciences, Aston University, Birmingham, UK

(Received 2 June 2010; and in revised form 6 September 2010)

Abstract The exchange of proteins and lipids between the trans-Golgi network (TGN) and the endosomal system requires multiple cellular machines, whose activities are coordinated in space and time to generate pleomorphic, tubulo-vesicular carriers that deliver their content to their target compartments. These machines and their associated protein networks are recruited and/ or activated on specific membrane domains where they select proteins and lipids into carriers, contribute to deform/ elongate and partition membrane domains using the mechanical forces generated by actin polymerization or movement along microtubules. The coordinated action of these protein networks contributes to regulate the dynamic state of multiple receptors recycling between the cell surface, endosomes and the TGN, to maintain cell homeostasis as exemplified by the biogenesis of lysosomes and related organelles, and to establish/maintain cell polarity. The dynamic assembly and disassembly of these protein networks mediating the exchange of membrane domains between the TGN and endosomes regulates cell- cell signalling and thus the development of multi-cellular organisms. Somatic mutations in single network components lead to changes in transport dynamics that may contribute to pathological modifications underlying several human diseases such as mental retardation.

Keywords: Assembly proteins, retromer, clathrin, trans-Golgi network, endosome, membrane trafﬁc

Introduction the cell surface or to the TGN, a retrieval pathway also

For personal use only. used by several endocytosed molecules. In the TGN, The trans-Golgi network (TGN) is the last sorting VPS10 family receptors (e.g., sortilin or neurotensin station of the secretory pathway from which a plethora receptor 3) or LIMP-2 (Reczek et al. 2007) may also of soluble or membrane proteins and lipids are sorted account for the M6P-independent delivery of some into distinct domains for subsequent transport to dif- soluble lysosomal enzymes to the endosomal system. ferent destinations: the cell surface (apical and baso- The second class includes transmembrane proteins lateral in polarized cells), the endosomal system, destined to reside in lysosomes or in lysosome- secretory granules in endocrine cells, synaptic domains related organelles in pigmented cells, such as lyso- in neurons. somal membrane glycoproteins (LAMPs and LIMPs) Two major classes of transmembrane proteins are and melanosomal proteins. The cytoplasmic domains

Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10 sorted in the TGN for delivery to the endosomal of these transmembrane proteins contain single or system. The ﬁrst class comprises transmembrane multiple sorting motifs of different types: tyrosine proteins cycling between the TGN and endosomes, based motifs (YxxØ) and variations of acidic clusters such as the two mannose-6-phosphate receptors combined with di-Leucine motifs ([D/E]xxxL[L/I] or (MPRs), which deliver their bound lysosomal DxxLL) (Bonifacino and Traub 2003), (Braulke and enzymes to endosomes in a mannose 6-phosphate Bonifacino 2009). Here, we will give a general (M6P) dependent manner (Munier-Lehmann et al. overview of the machineries and mechanisms regu- 1996), (Ghosh et al. 2003). After unloading their lating the sorting and the exchange of these cargos bound ligands in endosomes, they return either to between the TGN and endosomes.

Correspondence: Prof. Bernard Hoﬂack, Biotechnology Center TU Dresden, Dresden, Germany. Tel: +49 351 463 40235. Fax: +49 351 463 40244. E-mail: bernard.hoﬂ[email protected] *Authors Mihaela Anitei and Thomas Wassmer contributed equally to the paper.

ISSN 0968-7688 print/ISSN 1464-5203 online 2010 Informa UK, Ltd. DOI: 10.3109/09687688.2010.522601 2 M. Anitei et al.

Sorting machineries mediating post-TGN AP-1 (Peden et al. 2004), thereby suggesting that transport to endosomes AP-3 binds the clathrin heavy chains with a lower affinity. Therefore, AP-3 would not drastically Heterotetrameric coat protein complexes known as compete with the ESCRT component hepatocyte adaptor proteins (AP-1, AP-2, AP-3 and AP-4) decode growth-factor-regulated tyrosine kinase substrate Hrs, the sorting motifs in cargo tails, thereby segregating which binds clathrin efficiently (Raiborg et al. 2001) and cargos into transport carriers. Similar to other APs, could more easily segregate cargos into endosomal the ubiquitous AP-1A adaptor protein complex consists membrane domains distinct from those containing ubi- of four subunits (b1, g, m1a and s1); m1 recognizes quitinated proteins destined to be degraded in multi- tyrosine-based-motifs whereas a g/s1 hemicomplex vesicular bodies (Raiborg et al. 2002) (Figure 1). binds[D/E]xxxL[L/I]signatures(BonifacinoandTraub In specialized cells, AP-1 and AP-3 isoforms have 2003), (Janvier et al. 2003). A class of monomeric slightly different functions. In epithelial cells, the clathrin adaptors termed GGAs [Golgi-localized, AP-1B complex (containing a m1B subunit) targets gamma-ear containing, ARF (ADP ribosylation fac- specific cargos from recycling endosomes to the baso- tor)-binding proteins], including GGA1, GGA2 and lateral plasma membrane (Folsch et al. 2003), as does GGA3, with similar sorting functions, bind acidic AP-4 (Bonifacino and Traub 2003). Neuronal cluster-dileucine motifs through a VHS domain (Boni- AP-3 isoforms and AP-1 s1B regulate the synaptic facino 2004). Although AP-1A and GGAs cooperate in vesicle cycle (Newell-Litwa et al. 2007), (Glyvuk et al. cargo selection (Doray et al. 2002), their relative func- 2010). tions are not yet fully understood. GGAs have been detected both on the same or different clathrin/ AP-1-coated domains of the TGN but have not been Interaction of coat components with detected in purified clathrin-coated carriers, possibly membrane microdomains due to their unstable association with TGN membranes (Hirst et al. 2001), (2009), (Doray et al. 2002), The accuracy of membrane traffic depends upon orga- (Mardones et al. 2007). Thus, it has been suggested that nelles being correctly recognized by coat components. GGAs function prior to AP-1 in protein sorting The recruitment of adaptor proteins onto specificmem- (Hirst et al. 2001), (Doray et al. 2002) or that they brane microdomains relies on the combinatorial use of function in parallel pathways (Mardones et al. 2007), multiplelow-affinity,sometimesshort-lived,membrane (Hirst et al. 2009). The VHS and GAT domains of at components, which comprise an active, GTP- least GGA3 bind ubiquitin (Puertollano and Bonifacino bound ARF-1 GTPase, phosphatidylinositide (PIs) 2004), (Scott et al. 2004). Therefore, GGAs may have a and sorting motifs in cargo tails (Baust et al. 2006). For personal use only. more specific role in sorting ubiquitinated cargos at ARF-1, which cycles between an inactive, the TGN for subsequent transport to endosomes, GDP-bound, cytosolic and an active, GTP-bound, where the endosomal sorting complexes required for membrane-associated form, functions as a general reg- transport (ESCRT complexes), which also bind ubiqui- ulator of AP-1, GGAs and AP-3 coat association tinated cargos, could sort them into nascent multivesi- (D’Souza-Schorey and Chavrier 2006). Therefore, cular bodies for subsequent degradation (David 2007). pathway-specific local nucleotide exchange and hydro- A second coat mediating transport of cargos to lyso- lysis on ARF-1 must rely on the recruitment of specific some and lysosome-related organelles (e.g., melano- guanine nucleotide exchange factors(GEFs)(Casanova somes in pigmented cells) is AP-3 (Le Borgne and 2007) and GTPase-activating proteins (GAPs) to these Hoflack 1998), (Bonifacino and Traub 2003), which, membrane subdomains (Donaldson and Honda 2005), Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10 like AP-1A, binds tyrosine motifs via m3 and acidic (Spang et al. 2010). Thus, an ARF-1 GEF, BIG2, is di-leucine motifs via d/s3(Dell’Angelica et al. 1997), implicated in AP-1 and GGA1 membrane association (Janvier et al. 2003). It is not yet clear where (Shinotsuka et al. 2002), (Baust et al. 2006), AP-3 functions. Although most of AP-3 is found on (Ishizaki et al. 2008), whereas BIG1 is linked to endosomal tubular profiles(Pedenetal. 2004),itcannot AP-3-dependent transport (Baust et al. 2008). be excluded that AP-3 also functions at the TGN or that AGAP1 and AGAP2 associate with AP-3 and AP-1, AP-1 and AP-3 function sequentially. In yeast, respectively (Nie et al. 2003), and the clathrin heavy AP-3 does not appear to require clathrin association chain (CHC)-interacting SMAP-type GAP (SMAP2) for its function (Vowels and Payne 1998), (Peden et al. with AP-1 (Natsume et al. 2006). ARF GAPs may 2002).Inmammalshowever,AP-3can bind theclathrin exhibit a dual function; they favour vesicle uncoating heavy chain via its b3 subunit (Dell’Angelica et al. 1998) via ARF-1 hydrolysis in a manner analogous to Sec23 in and ultrastructural analyses have shown that AP-3 co- COP-II vesicle-mediated ER-to-Golgi transport localizes with clathrin, but to a much lower extent than (Bi et al. 2002) or, alternatively, control ARF-1 Transport between TGN and endosomes 3

A B

Plasma membrane Plasma membrane (AP1-B)

RE RE AP-2 AP-2 (AP1-B) TGN TGN EE EE GGA/Clathrin AP-1A/Clathrin AP-3 AP-1A/Clathrin Retromer ESCRT AP-3 TIP47, Rab9 Golgi LE Golgi LE

Lysosome Lysosome

Figure 1. Model of (A) anterograde and (B) retrograde trafficking pathways between the secretory and endocytic pathway. Clathrin/ AP-2-coated endocytic vesicles traffick between the plasma membrane and early endosomes (EE). At the trans-Golgi network (TGN), proteins are incorporated into distinct carriers coated with either clathrin/AP-1A or clathrin/GGAs or AP-3 to be transported to the endosomal system. In polarized epithelial cells, clathrin/AP-1B-coated carriers forming at the TGN and/or recycling endosomes (RE) transport their cargos to the basolateral plasma membrane. On early endosomes, AP-3 coats select their cargos for subsequent transport to late endosomes (LE), a step of membrane traffic, which involve a maturation process including the formation of multivesicular bodies. On early endosomes, the retromer complexes transport proteins back to the TGN. On late endosomes, some proteins are retrieved to the TGN via Rab9 and TIP47 positive carriers.

activation during coat binding and carrier biogenesis 2008). PI4KIIIb has also been detected on (Kliouchnikov et al. 2009). AP-1 coated membranes (Baust et al. 2006), but its PIs are critical determinants of membrane domain precise role remains to be clarified. PI3P levels on identity (De Matteis et al. 2005), (Di Paolo and De endosomes depend on class III PI3 kinase (yeast Camilli 2006). They contribute to the recruitment of Vps34) and phosphatases such as myotubularin coat components and PI-binding domain (e.g., (MTM1) and myotubularin related proteins (De ENTH, FYVE, PH, PX) containing proteins func- Matteis et al. 2005). The recruitment and the activity For personal use only. tioning in various aspects of carrier biogenesis of these PI-modifying enzymes are regulated by (Vicinanza et al. 2008). PI4P promotes adaptor ARF-1 and by their interactions with coat compo- recruitment on the TGN, while PI3P promotes that nents (Godi et al. 1999). of AP-3 on early endosomes. At the TGN, AP-1g (via Cargo content is important for stabilizing coats on a positively charged sequence), GGAs (via a phospho- membranes. Together with ARF-1 and PIs, cargos tyrosine binding domain) and Epsin R (via ENTH are essential for promoting the high affinity interac- domain) can all bind to PI4P (Hirst et al. 2003), tion of AP-1 and AP-3 (Baust et al. 2006), (2008), (Wang et al. 2003), (2007). Some ARFGAPs involved GGA (Hirst et al. 2007), as well as that of AP-2 in endo-lysosomal trafficking have PH domains, as do (Ehrlich et al. 2004) with membranes. The binding certain ARFGEFs (Vicinanza et al. 2008) and Rho- of cargo to AP-1 induces a conformational change in Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10 GEFs such as the Rac1 GEF RhoGEF7 (also known the AP-1 core domain enhancing its interaction with as b-PIX) (InterProScan, IPR001849 domain, http:// active ARF-1 (Lee et al. 2008). Recently, time- www.ebi.ac.uk/interpro/) and the Golgi-localized lapse imaging of live cells has illustrated a cargo- Cdc42 GEF FGD1 (PH and FYVE domains) dependent regulation of both the size and the (Egorov et al. 2009). Three PI4 kinases, PI4KIIa, dynamics of clathrin- and AP-2 coated endocytic PI4KIIb and PI4KIIIb, and a clathrin-associated carriers (Mettlen et al. 2010). PI4,5P2 phosphatase, OCRL1 (oculocerebrorenal syndrome of Lowe) (Choudhury et al. 2005), can regulate PI4P levels on Golgi membranes. PI4KIIa Carrier biogenesis during post-Golgi regulates AP-1 binding (Wang et al. 2003). However, transport: Early stages it also interacts with AP-3 (Craige et al. 2008), and its knock-down affects both AP-1-dependent MPR and The biogenesis of clathrin-, AP-1- and GGA-coated AP-3-dependent LAMP trafficking (Baust et al. carriers starts to be understood. In contrast, that of 4 M. Anitei et al.

AP-3-coated carriers, which may involve septins during various steps of carrier formation. As an (Baust et al. 2008), still remains elusive. AP-1- and example, the ENTH-containing Epsin R, found on GGA-dependent transport relies on the formation of TGN and endosomes binds AP-1, GGAs (Kalthoff pleomorphic tubulo-vesicular carriers (Puertollano et al. 2002), (Mills et al. 2003), (Chidambaram et al. et al. 2003), (Waguri et al. 2003). This involves 2004) and the SNARE Vt1b thus mediating fusion of different protein networks that must be spatially post-Golgi derived carriers with their target compart- and temporally coordinated in order to induce mem- ment (Hirst et al. 2004). Eps15 (EGFR pathway brane curvature, tubule formation, elongation and substrate clone 15) that contains, an Epsin 15 homol- fission (Figure 2). ogy (EH) domain also identified in g-synergin The first step in carrier biogenesis is the assembly of (Page et al. 1999), is associated with AP-1 on TGN a protein network able to bend a lipid bilayer in order to (Chi et al. 2008). generate a bud. Several proteins or complexes have The second step in clathrin/AP-1 carrier biogenesis been implicated in this process. A first complex is the is the elongation of membrane buds enriched in clathrin triskelion made of three clathrin heavy and ARF-1, PI4P, coat and ENTH/EH domain-containing light chains that interact with the AP-1b1 and GGAs proteins (Puertollano et al. 2003), (Waguri et al. 2003), via clathrin-box motives present in clathrin heavy (Polishchuk et al. 2006). These tubules display distinct chains (Gallusser and Kirchhausen 1993), (Puertol- regions (tip, surface and neck region, probably with lano et al. 2001). Clathrin triskelions can assemble into different lipid and protein compositions) (Idrissi et al. flat lattices or bended structures (Kirchhausen et al. 2008), (Liu et al. 2009). Several studies have illustrated 1997). In addition to clathrin triskelions, adaptor pro- the role of the actin cytoskeleton and Rho GTPases in teins also interact, via their terminal ear domains, with controlling the dynamics of post-Golgi traffic accessory proteins that can induce membrane curva- (Merrifield et al. 2002), (Kaksonen et al. 2003), ture via PI4P and clathrin-binding epsin N-terminal (Carreno et al. 2004) (Figure 2). For example, homology (ENTH) or AP180 N-terminal homology Rac1 controls MPR trafficking by activating (ANTH) domains (Legendre-Guillemin et al. 2004). OCRL1 (Faucherre et al. 2005) and the post-TGN Competition between different accessory proteins for trafficking of E-cadherin to the plasma membrane binding to adaptor proteins and/or clathrin may occur (Wang et al. 2005). Cdc42 together with its effectors

Cortactin Cargo Arp2/3 PI-4P ARF1 F-actin PI-4, 5-P2 Coat G-actin For personal use only. Microtubule HIP1R Bar Domain Protein Kinesin Actin nucleation Dynamin activator Gadkin Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10

Carrier formation Coat assembly Carrier elongation (Late stages) (Early stages)

Figure 2. Model of clathrin/AP-1-coated carrier formation on TGN membranes. ARF1, PI-4-P and sorting motifs in cargo tails recruit AP-1 and clathrin to specific membrane subdomains inducing membrane curvature. Actin nucleation complexes associate with CHC at the edges of the clathrin coats. These complexes activate the Arp2/3 complex and trigger actin polymerization, thereby providing the force necessary to initiate carrier tubulation. Tubulated membranes may then recruit BAR domain-containing proteins that interact with N-WASP to sustain further actin polymerization via Arp2/3. Inhibitors of actin polymerization (HIP1R) which bind to clathrin light chains may prevent actin polymerization on the surface of the clathrin coats. Gadkin links AP-1 coat with kinesins and with microtubules. Carrier fission is induced by dynamin linked to the actin cytoskeleton. Thus, actin and microtubules may provide the forces necessary during the late stages of tubule formation, fission and subsequent microtubule based transport. Transport between TGN and endosomes 5

ARHGAP10 and FGD1 regulates the exit of exocytic which binds both ARF-1 and Rac1 (Tarricone post-TGN carriers via Arp2/3-dependent actin nucle- et al. 2001). The precise mechanisms regulating the ation (Musch et al. 2001), (Dubois et al. 2005), recruitment of BAR domain proteins on the TGN (Egorov et al. 2009). A more recent study has illus- membranes remain however to be understood. At the trated how complexes made of CYFIP/Sra/Pir121, TGN, BAR domain proteins could be recruited via Abi1 and Nap1, which activate the Arp2/3 complex interactions with PI4P, as shown for the yeast Rho via WAVE/WASP (Neural Wiskott-Aldrich Syndrome GTPase-activating protein Rgd1p (Prouzet-Mauleon Protein) family members (Schenck et al. 2003), et al. 2008), or with PI4,5P2 whose presence at the (Innocenti et al. 2005), (Takenawa and Suetsugu TGN remains however to be established, even though 2007) promote the elongation of clathrin/AP-1 carriers a PI4P 5 kinase (Godi et al. 1999), (Jones et al. 2000) from the TGN (Anitei et al. 2010). These complexes and the OCRL PI4,5P2 phosphatase are recruited onto membranes via interactions between (Choudhury et al. 2005) are detected on these mem- CYFIP and the N-terminal domain of CHC accessible branes. While stabilizing nascent tubules, BAR at the edges of coated buds. CYFIP also binds domain containing proteins could also sustain actin Rac1 (Schenck et al. 2003), which is activated by polymerization due to their ability to bind N-WASP the GEF b-PIX, known to form PAK-regulated com- (Takenawa and Suetsugu 2007) (Figure 2). plexes with the ARF-1 GAP GITs (Zhao et al. 2000). The last step in the biogenesis of clathrin/ Thus, the CYFIP-containing complexes coordinate AP-1-coated carriers is their fission from TGN mem- ARF-1-dependent clathrin/AP-1 coat assembly and branes. This requires dynamin, a large GTPase Rac1-dependent actin polymerization necessary for recruited around the neck of the elongated carriers tubule elongation. At the same time, the huntingtin- where it provides the force necessary for constriction of interacting protein 1-related (HIP1R), which binds membranes (Mettlen et al. 2009) that are under a clathrin light chains accessible at the surface of clathrin tension likely provided by actin polymerization coats can inhibit actin polymerization at the surface of (Merrifield et al. 2005). Dynamin itself, via cortactin coated buds (Carreno et al. 2004), (Poupon et al. acting either directly or via N-WASP, may control 2008) (Figure 2). actin polymerization (Uruno et al. 2001), During carrier formation, membrane curvature (Schafer et al. 2002), (Weaver et al. 2002). In addition, must be induced and stabilized, a process also relying the BAR domain-containing syndapin 2, which binds on lipid modifying enzymes (De Matteis and Godi dynamin 2, could be involved in such processes 2004). For example, phospholipase D (PLD), acti- (Kessels et al. 2006). However, the order in which vated by ARF-1 and PI4,5P2, controls the synthesis these molecules are engaged is still unclear, since actin of phosphatidic acid (PtdOH) and diacylglycerol may be necessary for the dynamin 2 recruitment For personal use only. (DAG), which induce asymmetry in the lipid bilayer (Cao et al. 2005). Newly formed Post-TGN carriers and thus sustain carrier formation (Roth 2008). In are transported towards endosomes via microtubule turn, membrane curvature may control the availability tracks. Early work identified the kinesin KIF13A as an of active ARF-1 as seen for ArfGAP1, which interacts AP-1 b1 interactor (Nakagawa et al. 2000), preferentially with positively curved membranes (Delevoye et al. 2009). Recently, an interaction through its amphipathic lipid packing sensor (ALPS) between Gadkin/g-BAR, an AP-1-associated protein, motifs and regulates the formation of an ARF-1 gra- and KIF5 was identified (Neubrand et al. 2005), dient along tubules during COPI-dependent transport (Schmidt et al. 2009), (Maritzen et al. 2010). Mem- (Ambroggio et al. 2010). brane Rab GTPases may connect carriers with the molecular motors that mediate trafficking along actin Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10 filaments or microtubules (Stenmark 2009). Microtu- Carrier biogenesis during post-Golgi bule and associated motors may thus provide, together transport: Late stages with actin, the forces necessary for carrier elongation, fission and transport. Curved membranes are enriched in proteins with BAR/Bin/Amphiphysin/Rvs or LPS/Lipid Packing Sensor domains. These proteins can sense increased Sorting complexes organizing endosome to membrane curvature and also bend the lipid bilayer TGN retrieval in vitro (Itoh and De Camilli 2006). The recruitment of BAR domain proteins depends on their abi- Multiple routes can be used for the retrieval of com- lity to bind, possibly via additional domains, either ponents from endosomes back to the trans- to PI-containing membranes (Itoh et al. 2005), or to Golgi network and retrograde transport may occur small GTPases, like the Golgi-localized arfaptin, from both early and late endosomes (Pfeffer 2009). 6 M. Anitei et al.

These multiple retrograde transport routes can be to the TGN most likely through recycling endosomes distinguished by their molecular requirements, in (Bonifacino and Hurley 2008), (Seaman 2008), particular their sorting machineries (Bonifacino and (Attar and Cullen 2009). Originally identiﬁed in yeast Rojas 2006), (Johannes and Popoff 2008) (Figure 3). where it consists of ﬁve subunits (Vps5, Vps17, The retromer complex sorts a large variety of cargos Vps26, Vps29 and Vps35) (Seaman et al. 1998), it (MPR/VPS10-like- and signalling receptors) in early has become clear that the retromer composition is endosomes, and organizes their subsequent transport more complex in mammals, where seven subunits

Retromer cargo

Membrane SNX1/ SNX/ SNX2 SNX6 interacting subcomplex

VPS VPS VPS Cargo 29 29 35 interacting subcomplex

Rab 7 Rab 7

Dynein/ Dynactin complex

Microtubule

Force development/ movement For personal use only.

FAM21 FAM21/WASH Complex WASH

Actin filament

Arp2/3 Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10

Pinching off Process

Figure 3. Model for retromer mediated cargo selection and carrier formation. (A) The GTPase Rab 7 recruits the cargo selective subcomplex of the retromer formed by VPS26, VPS29 and VPS35 onto the endosomal membrane where it can engage with its cargo. The membrane interacting subcomplex formed by combinations of SNX1/SNX2 and SNX5/SNX6 is associated via its PI3P binding PX domains with the endosomal membrane. Association of the cargo selective with the membrane interacting subcomplex and possibly multimerisation of the two complexes could lead to the formation of a tubular subdomain of the endosomal membrane, for which the curvature sensing/inducing bar domains of the SNXes are thought to be crucial. Formation of a tubular domain is likely to be assisted by force development achieved through the coupling of the minus end directed dynein/dynactin motor complex to the retromer via SNX5/SNX6. (B) The WASH/FAM21 complex is recruited by the retromer followed by actin polymerisation and Arp2/3 complex mediated actin ﬁlament branching which could assist force development. Currently it is unclear how recruitment of dynamin or a dynamin like factor to accomplish membrane ﬁssion of the formed carrier is regulated (C). Transport between TGN and endosomes 7

support its function (SNX1, SNX2, SNX5, SNX6, membrane fission (Derivery et al. 2009), the following Vps26, Vps29 and Vps35) (Attar and Cullen 2009), scenario seems to emerge (Figure 3): Rab7 recruits (Wassmer et al. 2009). The functional retromer cargo selective sub-complexes on the endosomal consists of two sub-complexes, a cargo-binding membrane (Rojas et al. 2008), where they recognize sub-complex consisting of Vps26, Vps29 and Vps35 and bind cytoplasmic receptor tails. Membrane- and a membrane interacting one comprising Vps5 and interacting subcomplexes already present on PI3P- Vps17 in yeast (Seaman et al. 1998), and combina- rich endosomal membranes are recruited, followed by tions of SNX1, SNX2, SNX5 and SNX6 in mammals force generation by the dynein/dynactin motor com- (Wassmer et al. 2007), (2009). plex through interaction with SNX5/SNX6. The pull- The cargo-selective sub-complex (primarily via ing force could lead to formation of a tubular sub- Vps35), binds the cytosolic tails of numerous trans- domain of the endosome that is stabilized by multi- membrane receptors. Well-characterized cargos of the merization of cargo- and membrane-interacting sub- retromer are CD- and CI-MPR, sortilin, wntless and complexes. Recruitment of Wash/Fam21, Arp2/3 and SorLa (Attar and Cullen 2009). The membrane- associated factors at the base of these tubules leads to binding sub-complex (Vps5, Vps17, SNX1/2, the formation of a branched actin network and devel- SNX5/6) may be recruited onto endosomal membranes opment of shearing force. Scission factors like dyna- by a combination of PX-domains binding to PI3P (and min or EHD family proteins (Daumke et al. 2007), possibly PI3, 5P2) and BAR-domains sensing mem- (Gokool et al. 2007) could then separate tubular brane curvature of SNX1 (Carlton et al. 2004). Multi- membrane from the limiting endosomal membrane, merization of cargo-binding and membrane interacting followed by rapid, minus-end directed transport subcomplexes could thus achieve efficient cargo con- mediated by dynein/dynactin. centration and membrane deformation, a prerequisite In addition to the retromer complex, it has been for the formation of retromer-positive tubular carriers proposed that clathrin, epsinR (which binds AP-1g (Carlton et al. 2004), (Wassmer et al. 2007) (Figure 3). and the Vit1b SNARE), and dynamin (Lauvrak et al. Recent studies have revealed that the retromer can 2004), (Saint-Pol et al. 2004), as well as AP-1 regulate clathrin dynamics on endosomes: SNX-4, as (Robinson et al. 2010) mediate protein retrieval wellasSNX-1,SNX-2 andSNX-3interactwithclathrin from the early endosomes to the TGN. However, it heavy chain via a conserved motif present in PX- is still difficult to understand how the clathrin/ domain proteins (Skanland et al. 2009). SNX-1 associ- AP-1 coat could function both in retrograde and ates with the endosomal receptor-mediated endocytosis anterograde directions i.e. in two distinct membrane 8 (RME-8) protein which activates the clathrin uncoat- environments (reviewed in (Hinners and Tooze ing Hsc70toinhibitclathrinrecruitment on endosomes; 2003), (Johannes and Popoff 2008)) and why retro- For personal use only. in the absence of RME-8 and Hsp70, retrograde cargo grade transport from early endosomes would require transport from endosomes to the TGN is impaired two different sorting machineries. It is possible that (Popoff et al. 2009), (Shi et al. 2009). clathrin-AP-1 coat and the retromer complex select Both the microtubule and the actin cytoske- cargos destined to two different destinations, TGN letons support the retromer sorting function. The and recycling endosomes, respectively. membrane interacting sub-complex can bind the TIP47 and the late endosomal Rab 9 GTPase were p150glued/dynactin 1 subunit of dynein/dynactin the first components described to mediate the via SNX5 and SNX6, an interaction relevant for retrieval of the MPR from the late endosomes to efficient endosome to TGN transport (Wassmer the TGN (Diaz and Pfeffer 1998) (Carroll et al. et al. 2009). This link provides some mechanistic 2001), (Pfeffer 2009). TIP47 binds both MPR sorting Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10 insight into how cargo binding and concentration signals and Rab9. In addition Rab9 binds RhoBTB3, can be coupled to membrane deformation, carrier a protein with an ATPase activity (Espinosa et al. formation and ultimately carrier motility. The actin 2009). Although clearly important for MPR retrieval, nucleation factor Wash coordinates Fam21 and Arp2/ the precise function of RhoBTB3 is still unknown. In 3 recruitment at the base of endosomal retromer contrast to the retromer complex, TIP47 and decorated tubules (Gomez and Billadeau 2009). Rab9 were acquired late during evolution. This would This complex is important for efficient retromer suggest that TIP47 and Rab9 define a salvage pathway mediated recycling of the CI-MPR and may provide to ensure the quantitative recovery of the MPRs from the necessary shearing forces at the interface between the late endosomal system. More recently, TIP47 has retromer-coated tubules and the limiting endosomal also been involved in lipid droplet biogenesis membrane to assist fission (Gomez and Billadeau (Bulankina et al. 2009). Therefore, it remains to 2009). As a Wash protein containing complex may understand how TIP47 could fulfill these two differ- be of general relevance in catalyzing endosomal ent functions. 8 M. Anitei et al.

TGN-endosome trafficking, signalling and processes that shape development. These develop- development mental processes, as well as cellular homeostasis and functionality, depend on a plethora of signalling Many examples illustrate the relevance of trafficking pathways that need to be integrated. The dynamics of between the TGN and endosomes in key developmen- membrane traffic is also dependent on extracellular tal processes, as did the embryonic lethality of mice signals transmitted via plasma membrane receptors lacking either the AP-1g or m1a subunits (Zizioli et al. and relayed by the corresponding signalling cascades. 1999), (Meyer et al. 2000). A huge advance in the This notion comes from comprehensive analyses understanding of the mechanisms involved was the based on high throughput screening combining discovery of morphogens such as Wnt, released by RNA interference and automated, quantitative multi- certain cell types to form long range gradients in a parametric image analysis revealing the importance of developing organism, eliciting a reaction of morphogen signalling pathways such as Wnt, integrin/cell adhe- receiving cells in a concentration dependent manner. sion, transforming growth factor (TGF)-beta and In screens performed in Caenorhabditis elegans,retro- Notch for the endocytosis of transferrin and EGF mer subunits were identified as key components (Collinet et al. 2010). Little is actually known about required for the efficient release of wnt (Coudreuse the substrates of the kinases underlying these signal- et al. 2006), (Prasad and Clark 2006). Another impor- ling pathways and the information remains fragmen- tant step in the understanding of wnt release was the tary. For example, EGF-EGFR signalling modulates discovery that the wnt-binding, seven-pass transmem- GGA3 phosphorylation (Kametaka et al. 2005). brane receptor wntless/evi is necessary for secretion of Wnt3a signalling via Frizzled and Dishevelled recep- wnt (Banziger et al. 2006), (Bartscherer et al. 2006). tors may control PI4P levels by activating PI4KIIa Quickly it became clear that wntless/evi recycling by the (Qin et al. 2009). A major challenge will be to identify retromer is necessary for wnt release. In the absence of the substrates of key kinases to obtain a comprehen- functional retromer, wntless is lysosomally degraded sive understanding of how signalling cascades regu- and wnt release is thus abolished (Belenkaya et al. late membrane traffic. 2008), (Franch-Marro et al. 2008), (Pan et al. 2008), (Port et al. 2008), (Yang et al. 2008). One possible interpretation of this data could be that wntless TGN-endosome trafficking and human associates with wnt at the level of the Golgi and diseases mediates its transport to the plasma membrane where wnt is released. Wntless undergoes endocytosis medi- The characterization of the cellular machineries mediated by AP-2 (Pan et al. 2008) and is then recycled to ating the bidirectional transport between the TGN For personal use only. the TGN by retromer, ready for another round of wnt and the endosomal system and the dissection of their delivery (Lorenowicz and Korswagen 2009). means of interaction and regulation are now shedding Another type of signalling pathway that regulates light onto the molecular bases of some human dis- development involves the proper intracellular traffick- eases. Improper clathrin/AP-1 dependent sorting ing of the Notch receptor and its ligand Delta. Plasma appears to be associated with mental retardation in membrane Notch receptors are endocytosed and then humans. Somatic mutations in AP-1s2 (Tarpey et al. sorted in early endosomes, at least partially via the 2006) as well as in clathrin/AP-1 coat associated ESCRT complex (Vaccari and Bilder 2005): Acti- CYFIP (Schenck et al. 2001) or p21-activated kinase 3 vated receptors are directed towards lysosomes, (PAK3) (Allen et al. 1998), (Baust et al. 2006) have whereas unactivated receptors are transported to recy- been associated with X-linked mental retardation. Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10 cling endosomes from where they can be again Furthermore, CYFIP, which coordinates ARF-1 recruited to the plasma membrane (Fortini and Bilder and Rac1 signalling for generating clathrin/AP-1 2009). In Drosophila melanogaster, the transport of the transport carriers, provides a direct link between Delta/Serrate/Lag2 (DSL) Notch ligand, depends on this pathway and the fragile-X mental retardation a homolog of Epsin R, Liquid facets (Wang and protein (FMRP), the most commonly affected mol- Struhl 2004) essential for cellular proliferation and ecule in this mental retardation syndrome differentiation (Lee et al. 2009). Moreover, the acti- (Schenck et al. 2003), (Anitei et al. 2010). This vation of the Notch receptor may also occur on suggests that membrane transport steps regulated intracellular membranes, mediated, for example, by by these molecules found in the same protein network binding to DLL3, a Golgi-associated Notch ligand (Baust et al. 2006) contribute, if only partially, to (Geffers et al. 2007). neuronal differentiation and functionality. Recent These are just two of the numerous examples that data points towards specific neuronal trafficking steps illustrate the impact of trafficking on signalling affected in the absence of these molecules. The Transport between TGN and endosomes 9

synaptic vesicle cycle is impaired in AP-1s1B-/- mice thus seriously limiting our possibilities of fully (Glyvuk et al. 2010). In the post-synaptic compart- understanding the process. In vitro reconstitution ment, functional FMRP is necessary for the traffick- approaches using giant unilamellar synthetic mem- ing of the AMPA glutamate receptors 1 and branes and measuring protein interactions in time and 5 (Nakamoto et al. 2007) that are recruited to the space may help in addressing these questions. cell surface from recycling endosomes, in an AP-1m Another important question is how antero- and ret- and Rab11-dependent manner (Correia et al. 2008), rograde transport steps are regulated and what dif- (Margeta et al. 2009). ferential regulation mechanisms are used in different A proper bidirectional transport between the TGN tissues and cell types to ‘tweak’ the transport system to and the endosomal system is also relevant to serve a specialized, tissue-specific function. However, Alzheimer’s disease. In affected patients, neurological besides these questions much more fundamental dysfunctions occur due to amyloid plaque accumu- issues persist. How many different retrograde routes lation. A central component of these plaques is amy- from endosomes to the TGN actually exist? How can loid b (Ab), a product of amyloid precursor protein directionality in transport from the TGN to endo- (APP) b-cleavage by b-site APP-cleaving enzyme somes be achieved when AP-1 can form carriers on (BACE). Both APP and BACE are transmembrane both compartments? Do AP-1 and AP-3 function in proteins trafficking between the TGN, endosomes mammalian cells in a parallel or a serial manner? and the plasma membrane; thus, the correct sorting Addressing these questions will be essential for under- of both the enzyme and its substrate are important for standing the principles that guide transport between b-processing (Small and Gandy 2006). FRET studies the biosynthetic and the endocytic pathways. Further- indicate that intracellular APP and BACE interact more, it will be essential to comprehensively under- mostly in early endosomes (Kinoshita et al. 2003), stand if and how the dynamics of the proteins favoring this compartment as the principal candidate networks involved in membrane trafficking is regu- for APP b-cleavage. Similar to depletion of GGA1, lated during, i.e., changes in environmental condi- GGA2 or GGA3, the knock-down of the Vps26 tions as seen during development or in certain subunit of the retromer resulted in BACE accumu- pathological conditions. lation in early endosomes (He et al. 2005). This is supported by recent data indicating that, in mice, the absence of retromer correlates with synaptic dysfunc- Acknowledgements tion and increased levels of Ab (Muhammad et al. 2008). However, it cannot be excluded that We thank the different lab members for their helpful discussions and critical comments. We apologize for b-processing also occurs in the TGN, especially since For personal use only. not being able to quote the work of many groups that APP binds not only AP1-B m1B, but also the AP-4 4 subunit and 4 depletion results in APP contributed to our current understanding of the traf- m m fi accumulation in the TGN with a simultaneous cking pathways described in this review. This work was supported in part by grants from DFG (TRR 83/ increase in Ab secretion (Icking et al. 2007), (Burgos et al. 2010). In conclusion, the full under- 1-2010, HO 2584/1-1, HO 2584/2-1, HO 2584/6-1, standing of the way APP and BACE cycle between HO 2584/8-1, HO 2584/9-1), and TU-Dresden. TGN, endosomes and the plasma membrane remains Declaration of interest: a challenge for the future. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Mol Membr Biol Downloaded from informahealthcare.com by Dr George Diallinas on 11/08/10 Concluding remarks

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