Clathrin‐Dependent or Not: Is It Still the Question?

Whether the endocytic uptake of a given molecule is mediated through clathrin‐coated pits or not is a classical criterion used to characterize its endocytic pathway(s). Hence, clathrin‐dependent endocytosis has been associated with highly selective and efficient uptake, whereas clathrin‐independent endocytosis appeared to be confined to bulk uptake of fluid‐phase markers. This scholastic view has recently been challenged using newly developed molecular tools that allow for the first time a functional and mechanistic analysis of these less well‐characterized clathrin‐independent pathways, including caveolar uptake and macropinocytosis. Furthermore, several studies point to a critical role of lateral lipid asymmetry – lipid rafts/microdomains – in membrane sorting. We will discuss the potential role of these structures in endocytosis and the possibility that differential sorting at the plasma membrane predisposes the ensuing intracellular fate of a given molecule as well as its physiological function.