CUBN

CUBN, or cubilin, is a large multiligand endocytic receptor encoded by the CUBN gene in humans. Cubilin is expressed on the apical surfaces of epithelial cells in the proximal tubule of the kidney and the enterocytes of the small intestine. It lacks a transmembrane domain and cytoplasmic tail; its membrane anchoring is mediated by amnionless (AMN) and, in kidney, by association with megalin (LRP2). The extracellular region contains multiple CUB and EGF-like domains that bind a variety of ligands including albumin, transferrin, retinol-binding protein, and the intrinsic factor–vitamin B12 complex.

In the kidney, cubilin forms a complex with megalin to reabsorb filtered proteins from the glomerular ultrafiltrate, aiding conservation of low molecular weight proteins and vitamins. In the intestine, cubilin, together with AMN, acts as the intrinsic factor–vitamin B12 receptor essential for the uptake of dietary vitamin B12, allowing endocytosis in the ileum.

Mutations in CUBN or AMN cause Imerslund-Gräsbeck syndrome (IGS), an autosomal recessive disorder characterized by selective B12 malabsorption leading to megaloblastic anemia, and mild to moderate proteinuria due to defective proximal tubule reabsorption. Diagnosis is by clinical features and genetic testing; management includes B12 supplementation.

From a research perspective, cubilin remains a focus for understanding receptor-mediated endocytosis in epithelial tissues and the pathophysiology of proteinuria, as well as potential implications for drug delivery and vitamin absorption disorders.