Endocytosis of membrane receptors: Two pathways are better than one

Endocytosis pathways are used by eukaryotic cells for internalization of nutrients, signal transduction regulation, and modulation of plasma membrane composition. The cytoplasmic regions of plasma membrane “cargo” proteins harbor signals that are recognized by “cargo adaptor” proteins; this concentrates the cargo proteins at sites of budding for subsequent internalization via an endocytic vesicle. There are several endocytic pathways that can mediate the internalization of many different cargo proteins. The best-studied pathway is clathrin-dependent endocytosis (CDE), defined by a requirement for the protein clathrin, which is the major component of the endocytic vesicle coat. There are multiple clathrin-independent endocytosis (CIE) pathways that generally depend on cholesterol-rich membrane domains (i.e., rafts, which can also be encased by the protein caveolin to form membrane invaginations called caveolae). Cargo internalization signals are short peptide motifs; yeast also uses posttranslationally conjugated ubiquitin (Ub) moieties (1). In this issue of PNAS, two studies show that Ub can act as an endocytic signal in mammalian cells; in the absence of clathrin, Ub can direct entry via a CIE pathway (2, 3). The idea that ubiquitylated cargo can travel via a CIE pathway was previously unrecognized, probably because the endocytic factors that can recognize and bind Ub (epsin and Eps15) were first shown to play key roles in the CDE pathway. Now, it seems that these endocytic factors may play multiple roles, depending on which signal the cargo protein presents, or which endocytic route is being used. In recent years it …