Startseite Lebenswissenschaften Getting to the right place at the right time – membrane trafficking and maturation in the endolysosomal system
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Getting to the right place at the right time – membrane trafficking and maturation in the endolysosomal system

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Veröffentlicht/Copyright: 29. Dezember 2025
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Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 406 Heft 10-12

Abstract

The endolysosomal system connects Golgi and plasma membrane to the degradative pathway towards the lysosome and therefore presents a crossroads for endocytic recycling, secretory transport and degradation. This complexity makes protein sorting and trafficking within the endolysosomal system challenging, and it requires tight regulation so that all proteins localize correctly. Proteins are sorted by distinct sorting adaptors, which recognize sorting signals and subsequently facilitate formation of transport carriers, which deliver content to other organelles. Alternatively, organelle maturation allows passive protein transport along different trafficking routes including endosomal and autophagosomal maturation. In this review, we will provide a bird’s eye overview of the divers routes along which proteins are transported within the endolysosomal system and highlight open questions in the field.

Keywords: adapter complexes; Arf; membrane trafficking; organelle maturation; Rab; small GTPases

1 Introduction

Eukaryotic cells have an elaborate endomembrane system including endoplasmic reticulum, Golgi apparatus with the associated trans-Golgi network (TGN), and the endolysosomal system. The endolysosomal system includes all organelles involved in degradative transport from the plasma membrane to the lysosome, and in the recycling of transmembrane receptors back to the TGN and plasma membrane (Klumperman and Raposo 2014). It also includes the catabolic autophagy pathway, at which end a mature autophagosome fuses with a lysosome. Protein transport and localization within the endolysosomal system depends on the combined action of selective membrane trafficking via transport intermediates that shuttle cargo between membranes and non-selective transport via organelle maturation.

Distinct protein trafficking routes connect endosomes with the plasma membrane, TGN and other endosomes. Along these routes selected proteins are sorted into small transport intermediates such as vesicles or tubules (Birgisdottir and Johansen 2020; Chen et al. 2017; Robinson 2015). Different adaptor proteins including heterotetrameric adaptor protein complexes (APs) and sorting nexins (SNX) collect specific cargoes and initiate formation of transport intermediates, which then undergo scission and ultimately become fusion competent to deliver their cargo to the target membrane (Cullen and Steinberg 2018).

Moreover, proteins can be non-selectively transported within maturing endosomes. The most prominent example of endosomal maturation is the transition of early endosome (EE) to late endosomes (LE) and then to lysosomes (Borchers et al. 2021). Autophagosomes undergo a very similar maturation process (Zhao and Zhang 2018), and also recycling endosomes (RE) change their membrane identity on their way back to the plasma membrane (D’Souza et al. 2014; Stockhammer et al. 2024a).

Within this review, we will focus on the different trafficking routes within the endolysosomal system. We will distinguish between trafficking pathways, which involve the formation of transport intermediates and those that rely on organelle maturation. The aim is to provide an overview on how the different organelles are connected and to highlight the molecular machineries involved in the transport processes. At the same time, we will point out open questions in the field.

2 Vesicular and tubular carriers in the endolysosomal system

For many years, transport between endosomes and other organelles was envisioned to occur in the form of small transport vesicles. Nowadays, we know that apart from vesicles, tubular transport intermediates and transient organelle-organelle-interactions through possible kiss-and-run mechanisms enable material exchange between organelles (Solinger et al. 2022; Sönnichsen et al. 2000; Stockhammer et al. 2024a). Regardless of the exact size or form of the transported cargo, all these processes require formation of a transport intermediate and fusion with a target membrane. While the mechanisms of carrier formation are in many cases still elusive, fusion requires large tethering complexes and SNARE proteins (Stanton and Hughson 2023).

Both processes depend on peripheral membrane proteins such as ARF and Rab GTPases, which recruit tethering complexes and membrane remodeling proteins and allow for rapid changes in membrane identity (Borchers et al. 2021; Brownfield and Fromme 2025; Wilmes and Kümmel 2023). ARFs have a myristoylated N-terminal amphipathic helix next to the GTPase domain (Randazzo et al. 1995). In the cytosol, ARFs are in the GDP-form and hide the myristoylated helix in a hydrophobic pocket (Liu et al. 2009). On their target membrane, ARF-specific guanine nucleotide exchange factors (GEF) promote GDP to GTP exchange, thus allowing the ARF proteins to insert their membrane anchors into the lipid bilayer. Only in the GTP-form, ARFs bind effectors such as adaptor proteins. A GTPase activating protein (GAP) provides the active site residues for the incomplete GTPase domain of ARFs (Sztul et al. 2019) and thereby allows GTP hydrolysis which reverses the process so that ARFs and recruited effectors are released from membranes (Thomas and Fromme 2020). Rab GTPases are regulated similarly, though depend on a GDP-dissociation inhibitor (GDI) to be kept soluble in the cytosol (Wilmes and Kümmel 2023). GDIs binds both the GTPase domain and the C-terminal prenyl anchor. A GDI can dissociate from the Rab-GDP to bind membranes, where a GEF induces nucleotide exchange. The Rab-GTP can then bind effectors such as tethering factors or phosphoinositide (PIP) kinases. Inactivation by a GAP is then followed by GDI-mediated extraction (Hiragi et al. 2022; Solinger et al. 2025; Wilmes and Kümmel 2023).

A pivotal step in the genesis of transport carriers is the presence and selection of cargo proteins (Sanger et al. 2019; Weeratunga et al. 2020). Different adaptor proteins recognize cargo proteins and coordinate cargo binding as well as coat and effector protein recruitment (Figure 1). Here, to provide an overview we divide the large group of endolysosomal cargo adaptors into “classical” adaptors, which include the adaptor protein complexes AP-1 to AP-5 and GGAs (Golgi-localized, γ-ear-containing, Arf (ADP-ribosylation factor)-binding proteins) and into SNX-based cargo adaptors such as retromer and retriever.

Figure 1: Overview of trafficking and maturation pathways in the endolysosomal system. Transport in the endolysosomal system either occurs passively via organelle maturation or via active transport in transport carriers. Maturation pathways are distinguished between endosomal maturation, autophagosomal maturation or maturation of recycling carriers (maturation pathways shown by blue arrows together with associated Rab and ARF membrane markers). Various adaptors organize trafficking via transport carriers between organelles. Transport pathways shown by red arrows, associated adaptor proteins are indicated.
Figure 1:

Overview of trafficking and maturation pathways in the endolysosomal system. Transport in the endolysosomal system either occurs passively via organelle maturation or via active transport in transport carriers. Maturation pathways are distinguished between endosomal maturation, autophagosomal maturation or maturation of recycling carriers (maturation pathways shown by blue arrows together with associated Rab and ARF membrane markers). Various adaptors organize trafficking via transport carriers between organelles. Transport pathways shown by red arrows, associated adaptor proteins are indicated.

2.1 Classical adaptors in the endolysosomal system

The five heterotetrameric adaptor protein complexes (AP-1, AP-2, AP-3, AP-4 and AP-5) collect cargo on various membranes of the endolysosomal system as well as at the Golgi apparatus and at the plasma membrane. Here, we will solely focus on the role of APs in the context of endolysosomal transport and maturation, as molecular architecture, cargo binding properties and their relevance in disease have been reviewed elsewhere (Guardia et al. 2018; Park and Guo 2014; Sanger et al. 2019).

Membrane recruitment and activation of APs is regulated by a combination of different membrane properties including the presence of (1) cargo molecules, (2) the small GTPase ARF1, or (3) specific PIPs. AP-1, AP-3 and AP-4 are recruited to membranes by ARF1, while AP-2 and AP-5 have a strong PIP requirement for membrane association (Sanger et al. 2019). AP-2 relies on phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) for membrane recruitment (Abe et al. 2008), and the AP-5-associated protein SPG15 has a FYVE domain that binds phosphatidylinositol 3-phosphate (PI3P) (Hirst et al. 2021). For AP-1 and AP-3, PI3P or PI4P enhance membrane binding (Schoppe et al. 2021). Importantly, cargo availability and binding is a prerequisite for recruitment and/or activation of APs (Kadlecova et al. 2016; Schoppe et al. 2021) and thus tightly controls AP-function in vivo. Therefore, the presence of those factors (ARF1, PIPs and cargo) dictates, to which membranes APs are recruited. By a combination of microscopical visualization of APs in fixed and living cells using different marker proteins, it was possible to determine the starting points of different AP-sorting routes (Hirst et al. 2013b; Huang et al. 2019; Mattera et al. 2017; Peden et al. 2004; Stockhammer et al. 2024a). However, defining the endpoint of a certain AP pathway has been difficult as it is technically challenging to follow single transport vehicles along their entire pathway. To circumvent this limitation, the flow of AP-specific cargoes has been monitored in disrupted systems, where either the cargo was trapped and rapidly released or where fusion was inhibited (Hirst et al. 2012; Navarro Negredo et al. 2017; Robinson et al. 2024; Stockhammer et al. 2024a). While this improved our understanding for which trafficking pathways certain APs are relevant, it did not reveal to which membrane the AP transport carriers fuse as their transport could be coupled to other sorting pathways or maturation processes. A more direct approach to identify the target membranes lies in the identification of tethering and fusion machinery that directly binds the AP transport vehicle and mediates its fusion to the target organelle. Here, mass-spectrometry based approaches helped to identify potential candidate proteins (Cattin-Ortolá et al. 2024; Schoppe et al. 2020; Stockhammer et al. 2024b). However, additional work is required to understand localization and function of those candidates.

Among the AP-pathways, the AP-2 pathway is understood best (Chen and Schmid 2020). AP-2 is recruited to the plasma membrane by PI(4,5)P2, which requires the phosphatidylinositol-4-phosphate 5-kinase (PIP5K1C) (Krauss et al. 2003). Cargo binding of AP-2 enhances its interaction with clathrin and leads to the formation of a clathrin-coated endocytic vesicle (Jackson et al. 2010; Kadlecova et al. 2016; Partlow et al. 2022). After dynamin-mediated fission, the vesicle fuses to EEs. Intriguingly, Rab5 is relevant for the uncoating of AP-2 vesicles, fueling the idea that uncoating of AP-2 vesicles is directly coupled to their fusion to the endosome (Semerdjieva et al. 2008). Yet, how such fusion process is coordinated and which machinery is involved is currently unclear.

The only AP that is present in all sequenced eukaryotic genomes is AP-1 (Hirst et al. 2011). AP-1 localizes to the TGN as well as on peripheral recycling compartments and in either case recruits clathrin to form vesicular buds (Peden et al. 2004; Stockhammer et al. 2024a). Membrane recruitment of AP-1 depends on ARF1 and PI(4)P (Ren et al. 2013; Schoppe et al. 2021), which also recruit AP-1 interactors such as EpsinR or GGAs (Bai et al. 2004; Mills et al. 2003). Despite its localizing to two distinct locations, the TGN and recycling compartments, AP-1 is considered to function as a retrograde acting adaptor that transports proteins from post-Golgi compartments back to the TGN (Robinson et al. 2024). WDR11 and its partner TBC1D23 are possible tethers for the AP-1 coated carriers at the TGN (Navarro Negredo et al. 2018). Why AP-1 is recruited to the TGN remains in this context of its retrograde function unclear. It is possible that AP-1 directly captures TGN-resident protein before they escape the TGN, similar to the proposed role of COPI on tubular transport intermediates that connect ER and Golgi (Weigel et al. 2021).

AP-3 localizes in higher eukaryotes to the same ARF1 recycling compartments as AP-1, but not to the TGN (Stockhammer et al. 2024a). In yeast, a direct Golgi to the lysosome-like vacuole AP-3 pathway has been described (Stepp et al. 1997). This led to the assumption that the AP-3 pathway in mammals would be organized similarly (Llinares et al. 2015). Indeed, the general function of AP-3 in transport of cargo proteins to the late endosome/lysosome seems to be conserved (Dell’Angelica et al. 1999; Peden et al. 2004). However, more recent data connects AP-3 function with endocytic recycling rather than Golgi export (Stockhammer et al. 2024a). In contrast to AP-1 and AP-2, AP-3 does not depend on clathrin as coat in vivo (Faúndez et al. 1998; Stockhammer et al. 2024a), despite the presence of a clathrin-binding box in its hinge domain (ter Haar et al. 2000). This raises the questions of how clathrin binding to adaptors is regulated if the presence of a binding site is not sufficient, and whether AP-3 requires a coat protein for its function. Also, it remains unclear into which membrane AP-3 transport carriers finally fuse in higher eukaryotes. In yeast, AP-3 interacts with the Vps41 subunit of the HOPS tethering complex (Angers and Merz 2009; Cabrera et al. 2010; Schoppe et al. 2020), which is required for all fusion events at the vacuole (Ungermann and Moeller 2025). In contrast, metazoan VPS41 failed to recruit AP-3 in mammalian cells (Sanzà et al. 2025), reinforcing the idea of divergent AP-3 pathways in yeast and metazoans.

Due to their later discovery, lower abundance and absence from several major model organisms including Saccharomyces cerevisiae the function of the other two adaptor protein complex AP-4 and AP-5 is less studied. AP-4 is recruited by ARF1 to the TGN where it is responsible for export of a small subset of cargo proteins, including the lipid scramblase ATG9A, which is a key protein in autophagy (Davies et al. 2018). AP-4 exports ATG9A into cytoplasmic vesicles, which are required for phagophore formation (Mattera et al. 2017). Tepsin as a possible AP-4 coat seems to support efficient vesicle delivery of ATG9A to phagophore membranes through interaction with mammalian ATG8-orthologue LC3B (Wallace et al. 2024). The fifth adaptor protein complex, AP-5, is the least understood (Sanger et al. 2019). In contrast to other APs, it exists as a heterohexamer instead of a heterotetramer with the two additional subunits SPG11 and SPG15 (Hirst et al. 2013a). Currently, no AP-5 specific cargo is known, but it has been speculated that AP-5 acts in retrieval of Golgi proteins from late endosomes and lysosomes and plays a role in autophagic lysosomal reformation (Hirst et al. 2018). AP-5 binds PI3P-positive membranes via its SPG15 subunit, but also requires GDP-bound Rag C (Hirst et al. 2021). Rag C couples AP-5 function to the mTORC pathway and explains the lysosomal localization of AP-5. How AP-5 acts mechanistically and which other proteins are needed for AP-5 transport is unknown.

Aside of the multimeric APs, GGAs are a family of monomeric adaptor proteins that are involved in transport from the TGN to endosomes. As their name suggests, GGAs bind to ARF1 and PI4P for membrane association, and interact with clathrin (Puertollano et al. 2001; Wang et al. 2007). Among other cargoes, they transport the cation-dependent and cation-independent mannose-6-phosphate receptors (MPR) (Ghosh et al. 2003), and bind the Rab5 GEF complex of EEs, the Rabaptin-5-Rabex-5 complex (Mattera et al. 2003). Thus, it is likely that GGAs coordinate TGN-EE trafficking by promoting Rab5 recruitment to GGA-positive vesicles. Noteworthy, GGAs can bind AP-1, and it has been suggested that both adaptors cooperatively act in cargo transport (Bai et al. 2004; Hirst et al. 2012). However, while AP-1 is believed to act retrograde, GGAs seem to act in an anterograde manner (Robinson et al. 2024). Therefore, the relevance of AP-1 binding for GGA function remains unclear.

2.2 SNX-based adaptors in the endolysosomal system

SNX proteins belong to a group of proteins characterized by the presence of a specific type of Phox homology (PX) domain, the SNX–PX domain. Almost all proteins with a PX-domain bind PI3P and consequently many of them are found on endosomal membranes (Chandra et al. 2019). In total, 33 SNX proteins have been identified in mammals, 12 of which contain an additional BAR domain (Hanley and Cooper 2021). The BAR domain senses or induces curvature (Simunovic et al. 2019), and neither the BAR domain nor the PX-domain by themselves are sufficient to localize SNX-BAR proteins to the correct membrane (Carlton et al. 2004). These proteins thus rely on coincidence detection of specific phosphoinositides and an appropriate degree of membrane curvature for best binding (Simunovic et al. 2019). Sorting nexins are involved in multiple endosomal trafficking pathways and can associate with the retromer and retriever sorting complexes (McNally and Cullen 2018).

Retromer was identified as heteropentameric complex in yeast, which retrieves transport receptors from LEs back to the TGN (Seaman et al. 1998). Here, two SNX-BAR proteins (Vps5 and Vps17) assemble with a trimer consisting of Vps26, Vps29 and Vps35. The trimeric core is conserved from yeast to mammals but does not form stable assemblies with the SNX-BAR proteins, and thus only the trimeric core is referred to as retromer in non-yeast systems (Burd and Cullen 2014; Swarbrick et al. 2011). In metazoan cells, multiple homologues exist for Vps5, named SNX1 and SNX2, and Vps17, named SNX5, SNX6 and SNX32 (McNally and Cullen 2018). They can form distinct SNX-BAR retromer complexes, and it is currently unclear, how the different SNX-BAR homologues control retromer function. In addition, retromer forms complexes with other SNX proteins that do not possess a SNX-BAR domain, including SNX3 and SNX27 (Harterink et al. 2011; Steinberg et al. 2013). While the SNX3-retromer transports cargoes retrograde from endosomes to the TGN, the SNX27-retromer sorts specific cargoes back to the cell surface (Harterink et al. 2011; Seaman 2021; Steinberg et al. 2013). In general, retromer recognizes its cargoes in combination with distinct SNX partners and then induces the formation of a transport intermediate (Leneva et al. 2021). For the SNX-BAR retromer, the BAR domains induce and stabilize membrane tubules, which then undergo restriction and finally scission (Gopaldass et al. 2023). How SNX3 and SNX27 retromer would remodel membranes to form endosomal carriers is elusive as they both lack a SNX-BAR domain. Furthermore, little is known how retromer-derived carriers fuse to their target membranes. For the SNX-BAR retromer, the Rab6-interacting protein-1 has been proposed as a SNX1-interacting tether at the TGN, suggesting that the retromer coat stays associated to the carrier until membrane recognition (Wassmer et al. 2009). In addition, GCC88 has been proposed as a tether for SNX3-retromer carriers (Cui et al. 2018), but which proteins mediate fusion und uncoating is unclear. Finally, retromer interacts with the β-propeller protein Atg18 (WIPI proteins in metazoan cells) (Courtellemont et al. 2022). This complex functions on LEs or lysosomes though specific cargoes remain to be identified.

The retriever complex is structurally homologous to retromer and consists of VPS26C, VPS35L and VPS29, which is present on both complexes (Boesch et al. 2024; McNally et al. 2017). Retriever acts together with SNX17 and the Commander complex in recycling of more than 120 different proteins from endosomes to the plasma membrane (McNally et al. 2017). Cargo binding to SNX17 enables the association with retriever which then leads to Commander-mediated recycling to the plasma membrane (Butkovič et al. 2024; Martín-González et al. 2025). Commander function is coupled to actin cytoskeleton reformation via the WASH complex (Butkovič et al. 2024), but how retriever-mediated carrier formation and fission would work and how cargoes are transported to the plasma membrane is not yet understood.

3 Organelle maturation in the endolysosomal pathway

A key principle in the endosomal system is organelle maturation. During this process, a membrane-enclosed organelle gradually changes its identity, thereby acquiring new functions and properties (Borchers et al. 2021; van der Beek and Klumperman 2025). Organelle maturation is regulated by external cues and incoming and outgoing traffic, which in turn lead to changes in membrane identity through changes in lipid composition and membrane-associated marker proteins, including small GTPases (Langemeyer et al. 2020; Liu et al. 2012; Zhao et al. 2021). The most prominent and by far best studied maturation process within the cell is the maturation of EEs, which first become LEs and then further fuse with lysosomes (van der Beek and Klumperman 2025). Similarly, after their formation at ER contact sites, autophagosomes also mature before fusing with the lysosome (Zhao and Zhang 2018). Likewise, REs as organelles that transport endocytosed transmembrane-receptors back to the plasma membrane, mature during the transport process (Stockhammer et al. 2024a). An overview of the specific molecular machineries involved in the different maturation pathways is provided in Figure 2.

Figure 2: Maturation across in the endolysosomal system. Selected molecular machinery involved in membrane identity changes within the different endosomal maturation pathways is shown. Most importantly, different Rab and ARF proteins switch between GTP-bound membrane-associated state (green) and GDP-bound state (purple) and thus change membrane identity. PIP-kinases are recruited to the membranes and locally produce specific PIP-species (shown in orange). In autophagy, lipidated ATG8 provides a specific membrane identity and forms a hub for autophagy-specific proteins to bind. For details see text.
Figure 2:

Maturation across in the endolysosomal system. Selected molecular machinery involved in membrane identity changes within the different endosomal maturation pathways is shown. Most importantly, different Rab and ARF proteins switch between GTP-bound membrane-associated state (green) and GDP-bound state (purple) and thus change membrane identity. PIP-kinases are recruited to the membranes and locally produce specific PIP-species (shown in orange). In autophagy, lipidated ATG8 provides a specific membrane identity and forms a hub for autophagy-specific proteins to bind. For details see text.

3.1 Endosomal maturation

EEs are the central sorting hub for endocytosed material and defined by the presence of Rab5 and high levels of PI3P at their membrane (Borchers et al. 2021; van der Beek and Klumperman 2025). Incoming vesicles and carriers from the plasma membrane and from the TGN fuse with EEs. At the same time, new carriers are formed at tubular domains to mediate retrograde transport to the Golgi or recycling to the plasma membrane (Yong et al. 2022). The multiple transport steps can explain why EEs appear as an octopus-like structure in electron micrographs (Klumperman and Raposo 2014; van der Beek et al. 2021). Proteins that are destined for degradation or are not recognized by a specific cargo receptor remain in the EE and are retained during endosomal maturation. During this process, intraluminal vesicles (ILVs) are formed by ESCRT machinery and the octopus-like shape is lost (Ott et al. 2025). The morphological transition is accompanied by an exchange of Rab5 as a marker of EEs to Rab7 as a LE-specific Rab (Borchers et al. 2021). For this, the Rab7 GEF Mon1-Ccz1 binds to Rab5-GTP and PI3P on EEs, and in turn recruits and activates Rab7 (Borchers et al. 2023; Langemeyer et al. 2020). At the same time, Mon1-Ccz1 displaces the Rab5 GEF from the membrane, thus preventing further Rab5 recruitment (Poteryaev et al. 2010). In addition, the PI3-Kinase Vps34 is an effector of Rab5, and therefore PI3P synthesis is tightly connected with the state of endosomal maturation (Shin et al. 2005; Tremel et al. 2021). It remains unclear what triggers the Rab5-Rab7 switch. A potential mechanism could be based on the loss of ubiquitinated cargo proteins on the membrane when they are sorted into ILVs (Ott et al. 2025). This loss of ubiquitin on the endosomal surface may then weaken the Rab5 GEF association and promote Rab7 GEF activation (Miao et al. 2024; Ott et al. 2025). In the absence of ESCRTs, fusion of LEs with the vacuole or lysosome is delayed (Ott et al. 2025; Russell et al. 2012), showing that ESCRT function and formation of ILVs is directly coupled to endosome maturation. Interestingly, the conversion of Rab5 to Rab7 has also been connected to recruitment of retromer and thus retrograde transport of cargo to the TGN (Balderhaar et al. 2010; Liu et al. 2012; Rojas et al. 2008; Seaman et al. 2009). The exact connections of the plethora of events that occur during the maturation process are still elusive.

Once the maturation to the LE is complete, it fuses with a lysosome and forms a lysosomal compartment, which is often referred to as endolysosome (Birgisdottir and Johansen 2020). Fusion requires the hexameric tethering complex HOPS, which tethers and fuses LEs and lysosomes (Ungermann and Moeller 2025). While yeast HOPS binds the Rab7 homologue Ypt7 at both ends (Shvarev et al. 2022), mammalian HOPS binds to Rab2, Rab39 or the small GTPase ARL8 at opposite ends (Ding et al. 2019; Khatter et al. 2015; Zhang et al. 2023). It has been proposed that mammalian HOPS binds to lysosomes via ARL8, and recognizes Rab2 on LEs (Schleinitz et al. 2023). Furthermore, removal of Rab7 from the endolysosomal membrane might be required to ensure functional separation of late endosomes and lysosomes (Jongsma et al. 2020; Kumar et al. 2022). This could be directly linked to the fusion process, as HOPS has been connected to recruitment of the Rab7 GAP TBC1D15 (Jongsma et al. 2020). How HOPS function is coordinated with Rab7 GAP recruitment is not yet understood.

To regenerate lysosomes, which can fuse to late endosomes, mammalian endolysosomes undergo a process termed lysosomal reformation (Bissig et al. 2017). This describes a process, which includes tubulation of the lysosomal membrane and consecutive fission. It requires the production of PI(3,5)P2 by the phosphoinositide kinase PIKfyve and the activity of the lysosomal calcium channel TRMPL1 (Bissig et al. 2017; Dong et al. 2010; Miller et al. 2015). How lysosome fusion and lysosomal reformation are coordinated and which factors are involved is presently unclear.

3.2 Autophagosome maturation

Maturation of autophagosomes follows a comparable program as described for endosomal maturation. Autophagosomes are formed de novo at the so-called phagophore assembly sites (PAS) at the ER by a subset of autophagy related proteins (ATG proteins) (Hollenstein and Kraft 2020; Nakatogawa 2020). Nucleation and formation of the phagophore require fusion of ER- and Golgi-derived vesicles and is promoted by the ATG1-kinase complex as well as the class III PI3P kinase complex, and depend on the lipidation of LC3, a ubiquitin-like protein, to phosphatidylethanolamine (PE) (Hitomi et al. 2023; Ichimura et al. 2000). During expansion of autophagosomes, lipid flux via the bridge-like protein ATG2 and its cofactor ATG18 helps growth of the phagophore, which can then engulf cytoplasmic contents from single proteins to entire organelles (Osawa et al. 2019). Autophagosomal closure requires components of the ESCRT machinery (Li et al. 2025; Zhen et al. 2020). Mammals contain six ATG8 orthologues divided into LC3 subfamily and GABARAP subfamily. While LC3s mediate phagophore elongation, GABARAPs were suspected to act later during autophagosome sealing (Schaaf et al. 2016; Weidberg et al. 2010). Importantly, ATG8 proteins are also required for autophagosome maturation by recruiting the Mon1-Ccz1 GEF complex to the membrane and thus initiating Rab7 accumulation (Gao et al. 2018; Hegedűs et al. 2016; Herrmann et al. 2023). This process is comparable to the Rab5-Rab7 transition in endosomal maturation (Borchers et al. 2021). While in yeast the presence of the Rab7-like Ypt7 protein on the autophagosome is sufficient to mediate subsequent HOPS-mediated fusion with the vacuole (Gao et al. 2018), additional Rab2 acquisition is necessary for fusion of autophagosomes with lysosomes in mammals (Zhang et al. 2024). However, it is not yet understood how and when late endosomes and autophagomes acquire Rab2 to become fusion competent. Autophagosomal maturation includes several additional events, including the clearance of ATG8 and PI3P from the membrane, and the activation or acquisition of the autophagosome-specific SNARE YKT6 (Kraft and Reggiori 2024; Zhao and Zhang 2018). The ATG8-specific hydrolase ATG4 cleaves ATG8 from PE once autophagosomes are closed (Kauffman et al. 2018; Yu et al. 2012), whereas the myotubularin proteins remove PI3P (Allen et al. 2020; Cebollero et al. 2012). ATG4 is phosphorylated by the ATG1 kinase and kept inactive (Sánchez-Wandelmer et al. 2017). Once autophagosomes have closed, ATG1 is either released from the membrane or enclosed in the autophagosome lumen and thus ATG4 becomes active (Kraft and Reggiori 2024). Similarly, the autophagy-specific SNARE YKT6 is also phosphorylated by ATG1 in its SNARE domain, which inhibits its ability to engage in SNARE complexes as long as ATG1 is at the membrane (Barz et al. 2020; Gao et al. 2020). When ATG1 is removed, YKT6 is activated and fusion can occur (Licheva et al. 2022).

Mammalian lysosomes, which are formed by fusion of a lysosome and an autophagosome, are called autolysosomes, allowing distinction of lysosome based on their origin (Birgisdottir and Johansen 2020). Similar to endolysosomes, autolysosomes also undergo the process of lysosomal reformation.

3.3 Recycling endosome maturation

The least understood endosomal maturation pathway is the maturation of REs. Proteins that undergo endocytic recycling pass through the EE, but it is unclear how transport carriers that bring cargoes back to plasma membrane are formed at the EE. It is assumed that Rab4 plays a central role in the recycling process, which can either occur directly (fast recycling) or indirectly through REs (slow recycling) (Sönnichsen et al. 2000). What determines, which pathway is taken, remains unclear. It is possible that the retriever complex plays a role in carrier formation at the EE, but it is not known if it also participates in the genesis of recycling compartments. REs are defined by the presence of Rab11 and high levels of PI4P (Jani et al. 2022). Rab4 orchestrates a GTPase cascade, which includes the subsequent recruitment of ARL1 and ARF1 (D’Souza et al. 2014). Furthermore, ARF1 is later shed from recycling compartments, which then become Rab11 positive REs (Stockhammer et al. 2024a). Therefore, in the RE maturation pathway a possible Rab4-ARF1 switch is followed by an ARF1-Rab11 switch. Which cues trigger the acquisition and shedding of ARF1, and how Rab11 is recruited to REs is not understood. The presence of ARF1 might be necessary to recruit adaptors such as AP-1 and AP-3 to retrieve missorted proteins to their correct destinations (Robinson et al. 2024; Stockhammer et al. 2024a). In addition, both AP-1 and AP-3 recruit ARF1 GAPs (Nie et al. 2005; Schoppe et al. 2020), suggesting a connection between AP-driven transport and maturation. The life cycle of a RE ends with the fusion to the plasma membrane, which requires Rab11, a phosphoinositide conversion cascade, and the exocyst tethering complex (Maib and Murray 2022; Takahashi et al. 2012). How this process is precisely coordinated, is not yet clear.

4 Conclusions

Many of the key routes and molecular machinery within the endolysosomal system have already been identified; however, the current challenge lies in finding the connections between the different pathways. How are maturation and transport carrier pathways connected? For instance, retromer function is connected to the maturation process of EEs to LEs, and AP-1 has been observed at maturing REs (Rojas et al. 2008; Stockhammer et al. 2024a). In general, it is likely that cargo availability and maturation are tightly coupled, to allow only progression in a pathway once all proteins have been collected that are not supposed to go further. Thus, although vesicular trafficking and organelle maturation are distinct processes, they are interdependent. In- and outgoing transport changes composition of the organelle and consequently drives maturation. In turn, the change of membrane identity as a result of maturation allows binding of different sorting adaptors to enable vesicular sorting events (Casler and Glick 2020; Liu et al. 2012; van Weering et al. 2012). Moreover, the exact mechanisms and regulation of many trafficking and maturation steps are still elusive.

Finally, it is tempting to speculate that organelle maturation is a more general concept for all transport processes, ranging from Golgi maturation to transition processes at the TGN to the endolysosomal pathway (Casler and Glick 2020; Losev et al. 2006; Rink et al. 2005; Stockhammer et al. 2024a; Ueda et al. 2004). Many, if not all, maturation events include cascades of GEFs and GAPs, which coordinate Rab, ARF or ARL recruitment together with the corresponding PIP code.

Membrane trafficking results in a mixing of membranes from different sources. It has become clear that lipid transfer proteins function as a fueling and buffering system for all organelles in eukaryotic cells (Reinisch et al. 2025). Lipid transfer occurs at membrane contact sites, often at the ER, which spans the cell like a spider web and reaches every corner (Striepen and Voeltz 2023). The ER is also the place of lipid synthesis. In general, two systems function in supplying organelles with lipids. (i) ER-localized lipid transfer proteins (LTPs) transport individual lipids in exchange for another, often PI4P, which is discharged at the ER (Reinisch et al. 2025; Subra et al. 2023). (ii) Bridge-like proteins transport lipids along a lipid slide from one membrane to the other (Reinisch and Prinz 2021; Reinisch et al. 2025). We described here ATG2 at the ER-phagophore contact site, which provides up to 80 % of all lipids of the autophagosomes (Maeda et al. 2019; Osawa et al. 2019; Valverde et al. 2019). VPS13 proteins belong to the same family and connect the ER to endosomes, lysosomes and other organelles (Kumar et al. 2018; Suzuki et al. 2024; Yeshaw et al. 2019; Wang et al. 2025). In the endosomal pathway, VPS13 provide the lipids needed for efficient ESCRT function. To help lipid distribution between both leaflets, lipid scrambling occurs at both the donor and acceptor membrane. Many translocation proteins of the ER and other membranes can scramble lipids. At the phagophore, the ATG9 lipid scramblase cooperates with ATG2 (Noda 2021), whereas other lipid scramblases such as Any1 act at endosomes (Gao et al. 2025). While these lipid scrambling systems support organelle maturation, they can also support cells, when organelles are damaged to provide lipids to seal membranes (Wang et al. 2025). Excellent recent reviews highlight these processes in detail (Hanna et al. 2023; Reinisch and Prinz 2021).

Box 1: Lipid sorting along the endolysosomal pathway.

However, detailed future analyses are necessary to determine the specific order of events at membranes to understand how membrane trafficking mediates protein sorting and maintains organellar functions. In addition, lipid transport is closely linked to membrane traffic and maturation events as additional or specific lipids might be required for certain processes (Box 1), but the exact coordination of those events is in many cases unresolved. It remains challenging, yet also exciting, to unravel the molecular cues and events that determine the logistics of intracellular trafficking.

Corresponding author: Christian Ungermann, Department of Biology/Chemistry, Biochemistry section, Osnabrück University, Barbarastrasse 13, D-49076 Osnabrück, Germany; and Center of Cellular Nanoanalytics Osnabrück (CellNanOs), Osnabrück University, Barbarastrasse 11, D-49076 Osnabrück, Germany, E-mail:

Acknowledgments

We thank Lars Langemeyer for feedback.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: Alexander Stockhammer: writing and editing; Christian Ungermann: writing and final editing.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: This work was supported by grants of the DFG to C.U. (SFB 1557, DFG no. 516911046) and A.S. (Walter Benjamin support, DFG no. 564459937).

  7. Data availability: Not applicable.

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Received: 2025-08-01
Accepted: 2025-10-14
Published Online: 2025-12-29
Published in Print: 2025-12-17

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight: organelles on and off the map: diversity, specialization and subdomains
  3. Emerging dimensions of mitochondrial specialization
  4. Manipulating mitochondrial gene expression
  5. Conserved function, divergent evolution: mitochondrial outer membrane insertases across eukaryotes
  6. There and back again: a cell biologist’s journey from organelles to molecules
  7. Recent advances in glycosome biogenesis and its implications for drug discovery
  8. Jack of all trades – the lipid droplet organization (LDO) proteins are multifunctional organelle surface receptors
  9. Update on VAP, a ubiquitous signpost for the ER
  10. Biogenesis and function of the mitochondrial solute carrier (SLC25) family in yeast
  11. Getting to the right place at the right time – membrane trafficking and maturation in the endolysosomal system
https://doi.org/10.1515/hsz-2025-0187
Schlagwörter für diesen Artikel
adapter complexes; Arf; membrane trafficking; organelle maturation; Rab; small GTPases
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight: organelles on and off the map: diversity, specialization and subdomains
  3. Emerging dimensions of mitochondrial specialization
  4. Manipulating mitochondrial gene expression
  5. Conserved function, divergent evolution: mitochondrial outer membrane insertases across eukaryotes
  6. There and back again: a cell biologist’s journey from organelles to molecules
  7. Recent advances in glycosome biogenesis and its implications for drug discovery
  8. Jack of all trades – the lipid droplet organization (LDO) proteins are multifunctional organelle surface receptors
  9. Update on VAP, a ubiquitous signpost for the ER
  10. Biogenesis and function of the mitochondrial solute carrier (SLC25) family in yeast
  11. Getting to the right place at the right time – membrane trafficking and maturation in the endolysosomal system
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