cubilin

Cubilin is a large, multiligand endocytic receptor encoded by the CUBN gene and expressed on the apical surface of enterocytes in the small intestine and proximal tubule cells in the kidney. It is a peripheral membrane protein that lacks a transmembrane domain and is anchored to the cell surface through the transmembrane protein amnionless (AMN). In the kidney, cubilin forms a functional complex with AMN and with megalin (LRP2), enabling reabsorption of many filtered proteins from the glomerular filtrate. In the intestine, cubilin, together with AMN, binds intrinsic factor–vitamin B12 (IF–B12) complexes and mediates their uptake in the ileum, enabling dietary B12 absorption.

Structurally, cubilin comprises multiple CUB domains and epidermal growth factor–like repeats that enable binding of a broad range of ligands, including IF–B12, albumin, transferrin, retinol-binding protein, and other plasma proteins. The receptor's ligand repertoire contributes to protein reclamation in the kidney and to nutrient uptake in the gut.

Clinical significance: Mutations in CUBN cause Imerslund–Gräsbeck syndrome, a rare hereditary disorder characterized by selective vitamin B12 malabsorption and proteinuria, typically presenting in childhood. B12 deficiency leads to megaloblastic anemia; treatment with high-dose B12 is effective for systemic deficiency.

CUBN variants have also been investigated in certain proteinuric kidney diseases; their role is variable and under study.