Rapid transport of internalized p-selectin to late endosomes and the TGN: Roles in regulating cell surface expression and recycling to secretory granules

Prior studies on receptor recycling through late endosomes and the TGN have suggested that such traffic may be largely limited to specialized proteins that reside in these organelles. We present evidence that efficient recycl ing along this pathway is functionally important for nonresident proteins. P-selectin, a transmembrane cell adhesion protein involved in inflammation, is sorted from recycling cell surface receptors (e.g., low density lipopro tein [LDL] receptor) in endosomes, and is transported from the cell surface to the TGN with a half-time of 20-25 min, six to seven times faster than L DL receptor. Native P-selectin colocalizes with LDL, which is efficiently t ransported to lysosomes, for 20 min after internalization, but a deletion m utant deficient in endosomal sorting activity rapidly separates from the LD L pathway. Thus, P-selectin is sorted from LDL receptor in early endosomes, driving P-selectin rapidly into late endosomes. P-selectin then recycles t o the TGN as efficiently as other receptors. Thus, the primary effect of ea rly endosomal sorting of P-selectin is its rapid delivery to the TGN, with rapid turnover in lysosomes a secondary effect of frequent passage through late endosomes. This endosomal sorting event provides a mechanism for effic iently recycling secretory granule membrane proteins and, more generally, f or downregulating cell surface receptors.