The Enigmatic Endosome – Sorting the Ins and Outs of Endocytic Trafficking Naava Naslavsky1 and Steve Caplan1,2,*

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The Enigmatic Endosome – Sorting the Ins and Outs of Endocytic Trafficking Naava Naslavsky1 and Steve Caplan1,2,* © 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs216499. doi:10.1242/jcs.216499 REVIEW The enigmatic endosome – sorting the ins and outs of endocytic trafficking Naava Naslavsky1 and Steve Caplan1,2,* ABSTRACT nature remain unanswered. Even very basic questions regarding The early endosome (EE), also known as the sorting endosome (SE) the characterization of endosomes have yet to be satisfactorily is a crucial station for the sorting of cargoes, such as receptors and resolved (see Box 1). For example, are EEs a heterogeneous lipids, through the endocytic pathways. The term endosome relates to population of endosomes, each marked by an overlapping but the receptacle-like nature of this organelle, to which endocytosed different array of proteins? If so, do these different EEs carry out cargoes are funneled upon internalization from the plasma distinct functions, or are they a progressive series of endosomal ‘ ’ membrane. Having been delivered by the fusion of internalized structures along a pathway whereby the EE eventually evolves vesicles with the EE or SE, cargo molecules are then sorted to a into a more mature organelle? variety of endocytic pathways, including the endo-lysosomal pathway Additional key questions remain about the fundamental ways that for degradation, direct or rapid recycling to the plasma membrane, endosomes function. For example, a wealth of evidence supports the and to a slower recycling pathway that involves a specialized form of notion that EEs function by sorting cargo to distinct endosomal endosome known as a recycling endosome (RE), often localized to membrane domains that subsequently undergo budding and fission the perinuclear endocytic recycling compartment (ERC). It is striking and give rise to an array of tubulo-vesicular structures that transport that ‘the endosome’, which plays such essential cellular roles, cargo along microtubules to the perinuclear ERC (Grant and has managed to avoid a precise description, and its characteristics Donaldson, 2009; Jovic et al., 2010), which in itself is a poorly remain ambiguous and heterogeneous. Moreover, despite the rapid understood concept (Fig. 2A). However, it is also possible that EEs advances in scientific methodologies, including breakthroughs in are mobile, and can themselves undergo microtubule-dependent light microscopy, overall, the endosome remains poorly defined. directional transport to the ERC (endosome relocation; Fig. 2B) This Review will attempt to collate key characteristics of the different similar to the way peripheral lysosomes move to the cell center types of endosomes and provide a platform for discussion of this (Khatter et al., 2015), raising the possibility that, at least under unique and fascinating collection of organelles. Moreover, under- certain conditions, not all slow recycling cargo reaches the ERC via developed, poorly understood and important open questions will classic vesicular transport (budding, fission, transport and fusion). be discussed. Moreover, the ERC is a dense, crowded region of the cell that also includes the MTOC (Maxfield and McGraw, 2004). Accordingly, KEY WORDS: Budding, Early endosome, Fission, Late endosome, the complex organization of the ERC, and how its multitude of Recycling endosome, Sorting endosome tubular and vesicular membrane-bound structures coordinate recycling, is only beginning to be understood. Introduction The purpose of this Review is to provide an up-to-date The early endosome (EE), also known as the sorting endosome (SE) understanding of the enigmatic endosome, with a focus on the (hereafter EE), is the initial destination for material internalized EE, because this organelle represents the major crossroads for from the plasma membrane (reviewed in Jovic et al., 2010) (Fig. 1). endosomal activity. Less emphasis will be placed on the LE, The unique membrane-bound EE compartment is a major cellular because many excellent reviews have recently addressed this sorting station from which cargo molecules can either be trafficked organelle and the subsequent degradation pathways (Scott et al., 2014; to the late endosomes (LE) and lysosome for degradation, or be Frankel and Audhya, 2017). Important characteristics of EE, RE and returned to the plasma membrane by various routes. Some receptors LE will be outlined first, including atable of key proteins that localize to are recycled to the plasma membrane directly from the EE via a endosomes, which includes their proposed functions (Table 1). We will rapid recycling pathway, whereas other receptors are transported to then highlight recent findings that address the array of protein sorting more specialized recycling endosomes (REs), often clustered in the complexes that associate with EEs and direct trafficking events, perinuclear-localized endocytic recycling compartment (ERC) including the classical retromer, sorting nexins, Wiskott–Aldrich adjacent to the microtubule-organizing center (MTOC). syndrome protein and SCAR homolog (WASH), retriever and CCC Despite the vast number of studies that refer to the various types complexes. We will also showcase exciting recent studies that overturn and subtypes of endosomes, our understanding of the enigmatic the long-held assumption that endocytic recycling is primarily a default endosome remains limited, and fundamental questions about its pathway, whereby proteins, in the absence of selective signals to target them to degradation, are typically recycled. 1The Department of Biochemistry and Molecular Biology, The University of Early or sorting endosomes Nebraska Medical Center, Omaha, NE 68198, USA. 2The Fred and Pamela Buffett Cancer Center, The University of Nebraska Medical Center, Omaha, NE 68198, The EE is considered to be the first subcellular organelle with which USA. internalized vesicles fuse, and we will discuss below important characteristics that define EEs, the sorting and trafficking pathways *Author for correspondence ([email protected]) that originate from EEs, mechanisms for fusion of endosomes or S.C., 0000-0001-9445-4297 vesicles with endosomes, and the role of key endocytic protein Journal of Cell Science 1 REVIEW Journal of Cell Science (2018) 131, jcs216499. doi:10.1242/jcs.216499 Fig. 1. Overview of endocytic Cargo pathways. Once internalized from the plasma membrane, membrane- bound vesicles that carry receptors Cytosol from the cell surface fuse with the Fast Slow EEs. The EE serves as a sorting Internalization recycling recycling station from which either tubulo- vesicular carriers deliver cargo to the endo-lysosomal system for degradation, or cargoes are recycled directly or indirectly to the plasma Degradation membrane via the endocytic recycling compartment. MVB EE ERC Anterograde Retrograde transport transport Lysosome Secretion Golgi complexes, including the retromer and affiliated complexes, in the some phosphatidylinositol 4-monophosphate (PI4P) reside on regulation of endocytic trafficking. segregated membranes of endosomes in addition to PI3P (Giridharan et al., 2013; Yoshida et al., 2017). Second, EEs are Characteristics of the EE dynamic in movement and frequently undergo fusion with one A body of work has established several important characteristics of another and with incoming endocytic vesicles (Diaz et al., 1988). EEs. First, EEs have a limiting membrane bilayer that is enriched in Furthermore, EEs have a lumenal pH of ∼6.2, and their lumen is the phosphoinositide phosphatidylinositol 3-phosphate (PI3P), acidified through the function of a V-ATPase proton pump (Murphy often generated by the lipid kinase PI3P kinase (reviewed in et al., 1984). In addition, key proteins associated with EEs often Corvera et al., 1999; Kobayashi et al., 1998a). Recent studies contain the FYVE (called after several protein containing the suggest that phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and domain, namely Fab1, YOTB, Vac1 and EEA1) PI3P-binding domain (Gaullier et al., 1998; Kutateladze and Overduin, 2001; Stenmark et al., 2002). Among the mammalian FYVE-domain- containing proteins localized to EE are EEA1 and rabenosyn-5 (see Box 1. A challenge – the complex characterization of Table 1). Finally, a number of small GTP-binding Rab proteins endosomal compartments typically associate with EE in their GTP-bound state. These include One of the most daunting challenges, which represents a serious gap in members of the Rab4, Rab5, Rab10, Rab14, Rab21 and Rab22 the understanding of endosomes, is the difficulty in characterizing these organelles. On the one hand, as noted for LEs and lysosomes, there are family and others (Delevoye and Goud, 2015). not sufficiently distinctive membrane markers that allow researchers to distinguish between these organelles by light microscopy (Scott et al., The EE gets the cargo 2014). This necessitates either electron microscopy for visual The EE is the first endocytic structure that accepts the many types determination, or density gradients for enrichment and biochemical of receptors, lipid membranes and extracellular fluids that are analysis. On the other hand, it is often possible to distinguish between internalized by small vesicles through a variety of internalization various types of endosomes based on either the proteins associated with modes at the plasma membrane (Gruenberg et al., 1989). the outer bilayer of their surrounding membrane, or the selective phospholipids that are enriched in these membranes. For example, EE Essentially, the EE is a major sorting station and crossroad for
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