A Quarter Century of EHD Protein Research: From Endosomal Recycling to Ciliopathies.

Eps15 homology domain-containing proteins comprise a conserved family of membrane-remodeling ATPases that regulate endocytic trafficking, membrane fission, receptor recycling, primary ciliogenesis and membrane dynamics across eukaryotes. Since the initial identification of EHD1 and its Caenorhabditis elegans homolog RME-1 as regulators of endocytic recycling, research over the past quarter century has expanded the functional scope of EHD proteins far beyond classical receptor return to the plasma membrane. In mammals, EHD1, EHD2, EHD3, and EHD4 occupy overlapping but distinct cellular locations and regulate diverse processes including tubular recycling endosome fission, caveolae stabilization, primary ciliogenesis, centrosome duplication, cytokinesis, mitochondrial homeostasis, lipid droplet biology, and lipophagy. These cellular functions are supported by extensive studies in cultured cells and animal models, including mice, zebrafish, flies, worms, and plants, highlighting both conserved and specialized roles for EHD orthologs. EHD dysfunction has also been associated with a broad range of human diseases, including metabolic and cardiovascular disorders, inflammatory and infectious disease, neurologic conditions, cancer, and ciliopathies. Although many disease links remain correlative or model-based, the recent identification of an EHD1 founder mutation causing proteinuria, hearing loss, and polycystic kidney disease provides direct genetic evidence connecting EHD dysfunction to human pathology. This review summarizes 25 years of EHD research, emphasizing how EHD proteins coordinate membrane trafficking, organelle remodeling, and disease-relevant cellular physiology.