Pathways and mechanisms of endocytic recycling

Abstract

Endocytic recycling is coordinated with endocytic uptake to control the composition of the plasma membrane. Although much of our understanding of endocytic recycling has come from studies on the transferrin receptor, a protein internalized through clathrin-dependent endocytosis, increased interest in clathrin-independent endocytosis has led to the discovery of new endocytic recycling systems. Recent insights into the regulatory mechanisms that control endocytic recycling have focused on recycling through tubular carriers and the return to the cell surface of cargoes that enter cells through clathrin-independent mechanisms. Recent work emphasizes the importance of regulated recycling in processes as diverse as cytokinesis, cell adhesion, morphogenesis, cell fusion, learning and memory.

Figure 1. Pathways of endocytosis and endocytic recycling

Itinerary of cargo proteins entering cells by clathrin-dependent (blue cargo) and clathrin-independent (red cargo) endocytosis. Subsequent routing of cargo to the early endosome, juxtanuclear endocytic recycling compartment (ERC) and recycling endosomes is shown. Some cargo is selected in the early endosome by the ESCRT complex to enter the multivesicular body (MVB) pathway and onto late endosomes (dashed arrow). Clathrin-dependent cargo can recycle back to the cell surface via a rapid recycling pathway that requires Rab4 and Rab35. Both types of cargo can move from the early endosome to endocytic recycling compartment (ERC) by a process requiring Snx4, dynein, EHD3, Rab10, Rab22a and the Rab11 effectors FIP2, -3 and -5. From the ERC, recycling of both types of cargo requires Rab11, and recycling of clathrin-independent cargoes involves the generation of Rab8- and Rab22a-dependent distinctive tubules in addition to many other factors. Clathrin-dependent cargo may also recycle through these different pathways. Rab10, -11, -22 and -35 are associated with the tubular recycling endosome and, along with EHD1/RME-1, Alix and FIP2 are required for recycling. In the periphery, the tubules appear to break up into vesicles prior to fusing with the cell surface, a process requiring Arf6, Rab11, Par3, Cdc42 and cortical actin. This is a composite description of endocytic recycling and all of the components shown here may not be evident in a given cell type.

Figure 2. Recycling and cytokinesis

During anaphase, membrane is added to the cleavage furrow by recycling endosomes and Golgi-derived vesicles. During abscission, as depicted, the removal of ECT2 (not shown) from the central spindle complex allows binding of CYK-4 (not shown) to FIP3, which helps to recruit Rab11–GTP- and FIP3-positive recycling endosomes to the intercellular bridge. Transport to the bridge is mediated, at least in part, through association of kinesin-1 with recycling endosome adaptor protein JIP4. At the midbody, Arf6–GTP promotes fusion via interaction with FIP3 and the exocyst. Arf6–GTP also interacts with JIP4, promoting exit from the intercellular bridge via motor switching to the dynactin–dynein complex. Rab35–GTP also contributes to abscission, probably through contribution of early endosome (EE)-derived vesicles and appears to be important for phosphatidylinositol-4,5-bisphosphate accumulation at the midbody.

Figure 3. Endocytic recycling and long-term potentiation

In postsynaptic membranes, NMDA receptor (NMDA-R)-mediated long-term potentiation requires myosin Vb, a conformation-dependent binding partner of Rab11-FIP2. NMDA-R activation results in calcium influx, triggering activation of myosin Vb, and translocation of recycling endosomes and their cargo into the spine. This series of events increases spine membrane area and increases AMPA-R density on the spine surface. GIRK channel density on the spine surface is also increased, likely through the same or similar mechanisms. Final transport from the recycling endosome to the spine surface is mediated by Rab8.