Nance-Horan Syndrome-like 1 interacts with endophilin and Ena/VASP proteins to promote fast endophilin-mediated endocytosis

Endocytosis is crucial for various physiological processes, facilitating the uptake of membrane proteins and extracellular material. Fast endophilin-mediated endocytosis (FEME), driven by endophilin A (EndoA), enables clathrin-independent, ligand-induced receptor uptake at the leading edge of cells. Whilst F-actin polymerisation is essential for FEME, how actin dynamics are regulated at sites of FEME is unknown. NHSL1, a member of the Nance-Horan Syndrome protein family, localises to the leading edge of cells, where it regulates migration, and to vesicular puncta, where its function is undetermined. Here, we show that NHSL1 and its uncharacterised family member NHSL2 co-localise and engage in direct, multivalent interactions with EndoA. NHSL1 also binds Ena/VASP proteins, a family of actin elongators. NHSL1 promotes FEME in cells and its interactions with EndoA and Ena/VASP proteins are required for this function. Thus, NHSL1 may cooperate with EndoA and Ena/VASP proteins to control membrane invagination and actin polymerisation, thereby mediating FEME.