Bending the boundaries: the many facets of endophilin-As from membrane dynamics to disease

The endophilin-A proteins (EndoAs) are Bin/Amphiphysin/Rvs (BAR) domain proteins with key roles in both clathrin-mediated (CME) and clathrin-independent endocytosis (CIE). Humans have three differentially expressed EndoAs, EndoA1, -A2, and -A3, encoded by the SH3GL2/1/3 genes, respectively. Their functions primarily arise from their N-terminal BAR domain, which senses and induces local membrane curvature, and C-terminal SH3 domain, which mediates interactions with various proline-rich domain-containing partners. Among others, EndoA-mediated endocytosis coordinates synaptic vesicle recycling, as well as internalization of cell adhesion molecules, ligand-stimulated receptors, and pathogens. Consequently, EndoAs influence key cellular processes like neurotransmission, signaling, cell adhesion, and infection. Importantly, EndoA dysregulation has been observed in several pathologies, notably neurodegeneration, cardiovascular diseases, and cancer. This review provides an overview of the function and regulation of the EndoA proteins in CME and CIE, and explores their lesser-characterized involvement in other processes such as autophagy. It further addresses how these functions contribute to physiological processes and the development of pathologies, with a particular focus on cancer pathophysiology. Together, it emphasizes non-redundant roles of EndoA proteins in various cellular processes and highlights the complex relationship between membrane trafficking and diseases.