Pathways of clathrin-independent endocytosis

In addition to the classical clathrin-dependent mechanisms of endocytosis, there are several pathways that do not use a clathrin coat and are, therefore, referred to as clathrin-independent (CI) mechanisms.CI mechanisms of uptake have gained much attention with the realization that they have important roles in the regulation of cell growth and development as well as important implications in the study of certain diseases and pathogens.Two well-known CI mechanisms are the caveolar pathway and fluid-phase endocytosis. However, there is much debate concerning the number of distinct CI mechanisms that exist, the best cargo molecules for the study of a particular pathway, and the underlying protein machinery that regulates these pathways.To organize the extensive literature on CI endocytosis for the purpose of arriving at a mechanistic understanding, this Review classifies CI mechanisms as follows: first, on whether or not they are dynamin dependent and, second, according to the involvement of the small GTPases CDC42, RhoA or ARF6.Protein-based mechanisms (for example, ubiquitylation) and lipid-based mechanisms (for example, nanoscale clustering of lipid-tethered proteins) may both function in the selection of cargo for CI endocytosis.The mechanism of budding in the dynamin-independent pathways remains elusive; however, recent theoretical studies provide testable ideas in this area.