biostudies-literatureMoreno-Layseca PEuropean Research CouncilDBT/Wellcome Trust India AllianceCancer Foundation Finland sr1073-1084https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617174biostudies-literatureUnknown23(10)Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery-Arf1, IRSp53 and actin-and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route.Nature cell biologyCargo-specific recruitment in clathrin- and dynamin-independent endocytosis.PMC7617174IA/M/15/1/502018200084615258Disanza AMoreno-Layseca PGodbole RJacquemet GSelbach MAepfelbacher MZauber HSommer CAl-Akhrass HVeltel SCervero PRae JKronqvist PJantti NZConway JRWKallionpaa REParton RGMayor SOliveira-Ferrer LLinder SIvaska JScita GfalseCargo-specific recruitment in clathrin- and dynamin-independent endocytosis.Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery-Arf1, IRSp53 and actin-and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route.2021-01-01T00:00:00Z2021 Oct2026-04-22T03:15:23.99Z2025-04-03T23:18:44.785ZS-EPMC76171743461602410.1038/s41556-021-00767-x