Review
Endosome maturation, transport and functions

https://doi.org/10.1016/j.semcdb.2014.03.034Get rights and content

Highlights

  • Endosome organization function, biogenesis and differences across species are discussed.

  • Endosomes form two membrane networks connected by multivesicular transport intermediates.

  • The early endosome: main sorting station that controls membrane flow along recycling and degradation pathways.

  • The late endosome: central hub for incoming traffic and outgoing traffic and a key sensing/signaling platform.

Abstract

Efficient sorting of the material internalized by endocytosis is essential for key cellular functions and represents a, if not the, major trafficking pathway in mammalian cells. Incoming material – solutes, receptors and cargos, lipids and even pathogenic agents – are routed to various destinations within mammalian cells at two major sorting stations: the early and late endosome. The early endosome receives all manner of incoming material from the plasma membrane, as well as from the Golgi, and serves as an initial sorting nexus routing molecules back to the cell surface through recycling endosomes, to the trans-Golgi network by retrograde transport, or on to the late endosome/lysosome. The early endosome also regulates cell signaling, through the downregulation of internalized receptors, which are packaged into intralumenal vesicles that arise from inward invaginations of the limiting membrane. These multivesicular regions detach or mature from early endosomes and become free endocytic carrier vesicle/multivesicular body, which transports cargoes to late endosomes. The late endosome provides a central hub for incoming traffic from the endocytic, biosynthetic and autophagic pathways and outgoing traffic to the lysosomes, the Golgi complex or the plasma membrane. They also function as a key sensing/signaling platform that inform the cell about the nutrient situation. Herein we summarize the current understanding of the organization and functions of the endocytic pathway, differences across species, and the process of endosome maturation.

Introduction

In eukaryotic cells, endosomes play a central role in controlling the reutilization or degradation of membrane components, thus regulating fundamental processes, including nutrient uptake, immunity, signaling, adhesion, membrane turnover, and development. Components that have been endocytosed by several pathways are delivered to a common early endosome (EE) (Fig. 1). Housekeeping receptors and other proteins are recycled back to the plasma membrane (PM) directly or indirectly via the recycling endosome, while other molecules are routed toward the trans-Golgi network (TGN) or the lysosomes for degradation. By ensuring that membrane components that need to be reutilized are segregated from the ones that are targeted to the lysosomes, the EE functions as a key sorting station in the cell. Transport from early to late endosomes is also accompanied by major protein and lipid remodeling and concomitant changes in the endosomal lumenal milieu [1]. Most notably, the V-ATPase, a multi-subunit proton pump, is responsible for the acidification of EEs and late endosomes/lysosomes to pH values of ≈6.2 and ≈5.5/5.0 respectively – a process, which in turn controls many endo-lysosome functions, including receptor–ligand uncoupling, lysosome enzyme activity, and transport.

Prior to degradation, activated signaling receptors and other proteins that need to be downregulated can be sorted into lumenal invaginations of the EE membrane, which are pinched off as free cargo-containing intralumenal vesicles (ILVs). Vacuolar regions containing intralumenal vesicles (ILVs) detach, or mature, from early endosomes and become free MVBs (multivesicular bodies) or ECVs (endosomal carrier vesicles) (Fig. 1), which eventually fuse with the late endosomes (LEs). LEs serve as a second trafficking hub and sorting station in the endosomal system. Material including ILVs and their cargo can be packaged into lysosomes for degradation, but can also be routed toward other destinations – e.g. ILVs can be released extracellularly as exosomes upon endosome fusion with the PM [2], [3], [4]. LEs also function at a crossroad with the autophagy pathway, which, in addition to endocytosis and TGN-derived traffic, provides an additional, evolutionarily conserved, entry route in the endocytic pathway for the degradation of cytosolic components and organelles [5]. The autophagic process begins with the assembly of the autophagosome, a double membrane structure, which engulfs materials destined for degradation. Eventually, the autophagosome fuses with late endocytic organelles in order to acquire degradative capacity.

Section snippets

The early/recycling endosome network

Despite the complex and varied routes of endocytosis, all material entering the cell converges upon a single organelle – the early endosome (EE). This pleomorphic and persistent structure, at least in mammals, serves as the first and primary locus after internalization for the sorting of membrane-associated molecules and the transfer or dispatching of solutes (Fig. 1).

EEs and recycling endosomes show different acidification properties and contain selective subsets of lipids and proteins,

ECV/MVB: the multivesicular transport intermediate

While receptors and other proteins that are destined for the PM or TGN are collected in EE tubules via the retromer, ligands after receptor uncoupling, e.g. LDL, and endocytosed solutes distribute within the vesicular portions of the endosomes for transport toward lysosomes. Presumably, this process is controlled primarily by their low surface area-to-volume ratio of optimal for content transport, as opposed to the high surface area-to-volume ratio of tubules favorable for membrane transport.

The late endosome/lysosome network

LEs contain multivesicular regions, which unlike ECV/MVBs, are highly pleiomorphic, including multilamellar or mixed multivesicular/multilamellar regions depending on the cell type (Fig. 1). Although the biophysical and biochemical principles intrinsic to such diverse membrane organization and packing are not known, this situation likely reflects specialized functions of intralumenal membranes in protein/lipid transport and metabolism [2]. Moreover, in addition to endocytic membrane transport

Going forward

While understanding molecular mechanisms of endosome function will continue to require the in-depth analysis of individual proteins or protein complexes, unbiased strategies such as RNAi and compound screens are being used to obtain a comprehensive and quantitative view of the pathway [103], [104], [105], [106], [107], [108]. Attempts have also started to integrate our knowledge of the machinery and regulation of the endocytic pathway to create a working systems model. Toward this end, Collinet

Acknowledgments

Support was from the Swiss National Science Foundation (310030B_141173), the Swiss Sinergia Program (CRSII3_141956), the Polish-Swiss Research Programme (PSPB-094/2010), the Swiss National Centre of Competence in Research (NCCR) in Chemical Biology, and LipidX from the Swiss SystemsX.ch initiative, evaluated by the Swiss National Science Foundation.

References (110)

  • C. Chen et al.

    Snx3 regulates recycling of the transferrin receptor and iron assimilation

    Cell Metab

    (2013)
  • J. Rink et al.

    Rab conversion as a mechanism of progression from early to late endosomes

    Cell

    (2005)
  • D. Poteryaev et al.

    Identification of the switch in early-to-late endosome transition

    Cell

    (2010)
  • M.S. Marks et al.

    Lysosome-related organelles: unusual compartments become mainstream

    Curr Opin Cell Biol

    (2013)
  • C. Bissig et al.

    ALIX and the multivesicular endosome: ALIX in Wonderland

    Trends Cell Biol

    (2014)
  • J. Brotherus et al.

    Subcellular distributions of lipids in cultured BHK cells: evidence for the enrichment of lysobisphosphatidic acid and neutral lipids in lysosomes

    J Lipid Res

    (1977)
  • S.K. Rao et al.

    Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis

    J Biol Chem

    (2004)
  • H.J. Kwon et al.

    Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol

    Cell

    (2009)
  • E. Ikonen et al.

    Cellular pathology of Niemann-Pick type C disease

    Semin Cell Dev Biol

    (2004)
  • M.S. Brown et al.

    The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor

    Cell

    (1997)
  • Y. Sancak et al.

    Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids

    Cell

    (2010)
  • K. Kogan et al.

    Structural conservation of components in the amino acid sensing branch of the TOR pathway in yeast and mammals

    J Mol Biol

    (2010)
  • C.C. Scott et al.

    Ion flux and the function of endosomes and lysosomes: pH is just the start: the flux of ions across endosomal membranes influences endosome function not only through regulation of the luminal pH

    Bioessays

    (2011)
  • C. Bissig et al.

    Lipid sorting and multivesicular endosome biogenesis

    Cold Spring Harb Perspect Biol

    (2013)
  • J. Huotari et al.

    Endosome maturation

    EMBO J

    (2011)
  • G. Raposo et al.

    Extracellular vesicles: exosomes, microvesicles, and friends

    J Cell Biol

    (2013)
  • C.A. Lamb et al.

    The autophagosome: origins unknown, biogenesis complex

    Nat Rev Mol Cell Biol

    (2013)
  • J. Tooze et al.

    Tubular early endosomal networks in AtT20 and other cells

    J Cell Biol

    (1991)
  • W. Stoorvogel et al.

    A novel class of clathrin-coated vesicles budding from endosomes

    J Cell Biol

    (1996)
  • J. Gruenberg et al.

    Membrane traffic in endocytosis: insights from cell-free assays

    Annu Rev Cell Biol

    (1989)
  • J. Gruenberg

    The endocytic pathway: a mosaic of domains

    Nat Rev Mol Cell Biol

    (2001)
  • C. Raiborg et al.

    Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes

    Nat Cell Biol

    (2002)
  • V. Pons et al.

    Hrs and SNX3 functions in sorting and membrane invagination within multivesicular bodies

    PLoS Biol

    (2008)
  • M.T. Howes et al.

    Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells

    J Cell Biol

    (2010)
  • R.M. Steinman et al.

    Endocytosis and the recycling of plasma membrane

    J Cell Biol

    (1983)
  • J.L. Goldstein et al.

    Receptor-mediated endocytosis: concepts emerging from the LDL receptor system

    Annu Rev Cell Biol

    (1985)
  • T. Galvez et al.

    SnapShot: mammalian Rab proteins in endocytic trafficking

    Cell

    (2012)
  • M.N. Seaman

    The retromer complex – endosomal protein recycling and beyond

    J Cell Sci

    (2012)
  • F. Steinberg et al.

    A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport

    Nat Cell Biol

    (2013)
  • F. Coumailleau et al.

    Notch trafficking in Sara endosomes during asymmetric cell division

    Nature

    (2009)
  • T. Ohya et al.

    Reconstitution of Rab- and SNARE-dependent membrane fusion by synthetic endosomes

    Nature

    (2009)
  • J.A. Solinger et al.

    Tethering complexes in the endocytic pathway: CORVET and HOPS

    FEBS J

    (2013)
  • H.J. Balderhaar et al.

    The CORVET complex promotes tethering and fusion of Rab5/Vps21-positive membranes

    Proc Natl Acad Sci U S A

    (2013)
  • D. Chirivino et al.

    The ERM proteins interact with the HOPS complex to regulate the maturation of endosomes

    Mol Biol Cell

    (2011)
  • W.A. Dunn et al.

    Receptor-mediated endocytosis of epidermal growth factor by rat hepatocytes: receptor pathway

    J Cell Biol

    (1986)
  • S. Sigismund et al.

    Endocytosis and signaling: cell logistics shape the eukaryotic cell plan

    Physiol Rev

    (2012)
  • B. Brankatschk et al.

    Regulation of the EGF transcriptional response by endocytic sorting

    Sci Signal

    (2012)
  • L.P. Sousa et al.

    Suppression of EGFR endocytosis by dynamin depletion reveals that EGFR signaling occurs primarily at the plasma membrane

    Proc Natl Acad Sci U S A

    (2012)
  • H.W. Shin et al.

    An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway

    J Cell Biol

    (2005)
  • J.H. Hurley et al.

    Molecular mechanisms of ubiquitin-dependent membrane traffic

    Annu Rev Biophys

    (2011)
  • Cited by (0)

    1

    These authors contributed equally to the work.

    View full text