ReviewEndosome maturation, transport and functions
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.
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These authors contributed equally to the work.