Frustrated clathrin-mediated endocytosis – causes and possible functions

Clathrin-mediated endocytosis is the main entry route for most cell surface receptors and their ligands. It is regulated by clathrin-coated structures that are endowed with the ability to cluster receptors and to locally bend the plasma membrane, resulting in the formation of receptor-containing vesicles that bud into the cytoplasm. This canonical role of clathrin-coated structures has been shown to play a fundamental part in many different aspects of cell physiology. However, it has recently become clear that the ability of clathrin-coated structures to deform membranes can be perturbed. In addition to chemical or genetic alterations, numerous environmental conditions can physically prevent or slow down membrane bending and/or budding at clathrin-coated structures. The resulting 'frustrated endocytosis' is emerging as not merely a passive consequence, but one that actually fulfils some very specific and important cellular functions. In this Review, we provide an historical and defining perspective on frustrated endocytosis in the clathrin pathway of mammalian cells, before discussing its causes and highlighting the possible functional consequences in physiology and diseases.