Mertk mobilizes myosin II from the RPE cell periphery to sites of OS engulfment, where myosin II function is essential for the normal phagocytic ingestion of OS.
Sorting endosomes and the endocytic recycling compartment are critical intracellular stores for the rapid recycling of internalized membrane receptors to the cell surface in multiple cell types. However, the molecular mechanisms distinguishing fast receptor recycling from sorting endosomes and slow receptor recycling from the endocytic recycling compartment remain poorly understood. We previously reported that Rab15 differentially regulates transferrin receptor trafficking through sorting endosomes and the endocytic recycling compartment, suggesting a role for distinct Rab15-effector interactions at these endocytic compartments. In this study, we identified the novel protein Rab15 effector protein (REP15) as a binding partner for Rab15-GTP. REP15 is compartment specific, colocalizing with Rab15 and Rab11 on the endocytic recycling compartment but not with Rab15, Rab4, or early endosome antigen 1 on sorting endosomes. REP15 interacts directly with Rab15-GTP but not with Rab5 or Rab11. Consistent with its localization, REP15 overexpression and small interfering RNA-mediated depletion inhibited transferrin receptor recycling from the endocytic recycling compartment, without affecting receptor entry into or recycling from sorting endosomes. Our data identify REP15 as a compartment-specific protein for receptor recycling from the endocytic recycling compartment, highlighting that the rapid and slow modes of transferrin receptor recycling are mechanistically distinct pathways. INTRODUCTIONEarly endosomes comprise two distinct compartments identified primarily through trafficking studies using the transferrin receptor (TfR). At steady state, internalized TfR resides on sorting endosomes (SEs) and the endocytic recycling compartment (ERC) (Maxfield and McGraw, 2004). In SEs, the TfR is sorted for direct recycling back to the plasma membrane or transported to lysosomes via late endosomes for down-regulation (Yamashiro et al., 1984; Yamashiro and Maxfield, 1987a,b;Schmid et al., 1988;Ghosh et al., 1994). A second slower route for receptor recycling occurs from the ERC, after receptor transit through SEs (Sheff et al., 1999;Maxfield and McGraw, 2004). An emerging model suggests that in addition to sorting desensitized receptors for down-regulation, SEs and the ERC provide a local reserve of intracellular receptors for rapid delivery to the cell surface (Szekeres et al., 1998;Lin et al., 2000;Park et al., 2004).Rab GTPases are potent regulators of membrane trafficking events (reviewed in Somsel Rodman and WandingerNess, 2000;Stein et al., 2003). They are small monomeric GTPases that cycle between a GTP-bound and GDP-bound state, which is regulated through molecular interactions with guanine nucleotide exchange factors and GTPase activating proteins (reviewed in Pfeffer and Aivazian, 2004). Furthermore, rabs are generally compartment specific, functioning through effector molecules to regulate vesicle fusion, vesicle budding, receptor sorting, and cytoskeletal interactions (Somsel Rodman and Wandinger-Ness, 2000;Segev, 2001)...
Rab15 is a novel endocyticEndocytosis of cell surface receptors regulates both the intensity and duration of receptor signaling by controlling the location of signaling interactions and the desensitization and recycling of activated receptors (reviewed in Refs. 1 and 2). Accordingly, endocytic compartments are highly specialized both in terms of their organization and function. The early/ sorting endosome is a major trafficking compartment from which several trafficking pathways emerge. Recently, Rab GTPases have emerged as potent regulators of membrane trafficking through early/sorting endosomes. Rabs do not regulate membrane trafficking per se but function as regulatory throttles impacting the kinetics of membrane transport steps through the recruitment of specific effectors that in turn mediate membrane transport (reviewed in Refs. 3-5). For example, Rab5 mediates the internalization and fusion of incoming endocytic vesicles in vivo (6 -8) and the homotypic fusion of endosomes in vitro (8 -12). Overexpression of the constitutively active GTP-bound mutant Rab5-Q79L in baby hamster kidney cells results in a dramatic increase in fluid phase and receptormediated endocytosis and leads to formation of enlarged early/ sorting endosomes. Conversely, overexpression of GDP-bound Rab5 (S34N) reduces endocytic uptake and results in the formation of a diffuse network of small endocytic vesicles (6 -8).Following activation on endosome membranes, Rab5-GTP drives the organization of a specialized membrane domain with distinct functional characteristics (13-15). Rab5-GTP forms this domain by recruiting the phosphatidylinositol 3-kinase hVPs34, which catalyzes the local production of PI-3-phosphate (PI3P) 1 (16 -18). Rab5-GTP and hVPs34 activities are essential for the subsequent recruitment of rabenosyn-5 and the docking protein early endosome antigen (EEA1) to early endosomal membranes through PI3P (17-22). EEA1 also interacts directly with syntaxin 13, a SNARE implicated in the fusion of early endosomes (13,23). Thus a model is emerging in which Rab5-GTP functions as a regulatory protein, driving assembly of specific effector complexes on endosomal membranes leading to membrane fusion (24). Consistent with this model, the early endocytic GTPases, Rabs 4 and 11, have also been shown to organize into distinct domains on early endosomes through the local recruitment of effectors (14, 15). Moreover, Rab4 and Rab5 function are linked through the shared effectors rabaptin-5 (25) and rabenosyn-5 (15). Thus Rab-specific domains appear to coordinate endosomal trafficking directly by communicating via shared effector complexes.The early endocytic GTPase Rab15 exhibits distinct endocytic localization and activity. Rab15 distributes between two early endosomal compartments, colocalizing with Rabs 4 and 5 on early/sorting endosomes and with Rab11 on pericentriolar recycling endosomes (26). Overexpression of activated Rab15 (Rab15-GTP) inhibits both fluid phase and receptor-mediated endocytosis in vivo and the homotypic fusion of early e...
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