Abstract
Endocytic trafficking relies on highly localized events in cell membranes. Endocytosis involves the gathering of protein (cargo/receptor) at distinct plasma membrane locations defined by specific lipid and protein compositions. Simultaneously, the molecular machinery that drives invagination and eventually scission of the endocytic vesicle assembles at the very same place on the inner leaflet of the membrane. It is membrane heterogeneity – the existence of specific lipid and protein domains in localized regions of membranes – that creates the distinct molecular identity required for an endocytic event to occur precisely when and where it is required rather than at some random location within the plasma membrane. Accumulating evidence leads us to believe that the trafficking fate of internalized proteins is sealed following endocytosis, as this distinct membrane identity is preserved through the endocytic pathway, upon fusion of endocytic vesicles with early and sorting endosomes. In fact, just like at the plasma membrane, multiple domains coexist at the surface of these endosomes, regulating local membrane tubulation, fission and sorting to recycling pathways or to the trans-Golgi network via late endosomes. From here, membrane heterogeneity ensures that fusion events between intracellular vesicles and larger compartments are spatially regulated to promote the transport of cargoes to their intracellular destination.
Highlights
In most situations, cells respond to extracellular stimuli through the binding and activation of cell surface receptors to extracellular ligands
We focus on domains constituted of lipid species – phosphoinositides, cholesterol and phosphatidylserine – which most contribute to membrane heterogeneity during intracellular trafficking, yet the concepts we refer to are likely to extend to other lipid species in similar cellular processes
Membrane heterogeneity is a central regulator of cargo endocytosis and sorting
Summary
Cells respond to extracellular stimuli through the binding and activation of cell surface receptors to extracellular ligands. PIK3C2α is recruited to the clathrin lattice via interactions with clathrin and PI(4,5)P2, where it metabolizes PI(4,5)P2 to PI(3,4)P2 in conjunction with the 5-phosphatases ORCL and synaptojanin-1 (Posor et al, 2013; He et al, 2017; Schöneberg et al, 2017) This distinct phospholipid environment promotes the recruitment and activation of the BAR-domain containing protein SNX9 that interacts with actin-branching activators and dynamin (Figure 1D) (Posor et al, 2013; Lo et al, 2017; Schöneberg et al, 2017) and provides constricting force at the neck of the endocytic vesicle (Shin et al, 2008; Ferguson et al, 2009). Recruitment of the 5-phosphatase ORCL to the neck of the clathrin-coated pit by SNX9 immediately prior to fission further stimulates vesicle uncoating (Nández et al, 2014)
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