Swiprosin1 controls cargo-specific entry to clathrin and dynamin-independent endocytic pathway

The clathrin and dynamin-independent endocytic pathway (CLIC-GEEC) is the major route of internalization of a large fraction of glycosylphosphatidylinositol-anchored proteins (GPI-APs) and other cell surface receptors. Unlike the clathrin-dependent endocytic pathway, where adaptors recruited to the endocytic pit provide the clues to recruit specific cargo, the CLIC-GEEC pathway is considered to take up portions of the membrane without any specificity. Here, we identified actin-binding protein swiprosin1 as the first cargo adaptor for the CLIC-GEEC pathway. We found that swiprosin1 interacts with active Rab21, a known regulator of integrin endocytosis, and couples Rab21 and the integrin cargo to the CLIC-GEEC endocytic machinery. Our work also identified the previously unknown pathway by which Rab21 mediates integrin endocytosis and linked the CLIC-GEEC pathway to integrin-dependent cancer cell invasion.