The intrinsic factor–vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein

Abstract

Cubilin is the intestinal receptor for the endocytosis of intrinsic factor-vitamin B12. However, several lines of evidence, including a high expression in kidney and yolk sac, indicate it may have additional functions. We isolated apolipoprotein A-I (apoA-I), the main protein of high-density lipoprotein (HDL), using cubilin affinity chromatography. Surface plasmon resonance analysis demonstrated a high-affinity binding of apoA-I and HDL to cubilin, and cubilin-expressing yolk sac cells showed efficient 125I-HDL endocytosis that could be inhibited by IgG antibodies against apoA-I and cubilin. The physiological relevance of the cubilin-apoA-I interaction was further emphasized by urinary apoA-I loss in some known cases of functional cubilin deficiency. Therefore, cubilin is a receptor in epithelial apoA-I/HDL metabolism.

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

“…44,45 In addition to facilitating the absorption of the intrinsic factor-vitamin B 12 complex, cubilin is a high-affinity apolipoprotein A-I receptor that facilitates the endocytosis of high-density lipoprotein (HDL) holoparticles and their subsequent transport to endosomes/lysosomes where they are digested. 46,47 This endocytic process resembles that for low-density lipoproteins (LDL) and appears to involve the participation of the co-receptor megalin, a member of the LDL receptor family. [46][47][48] Moreover, cubilinmediated HDL endocytosis is inhabitable by apolipoproteins including A-I, A-II, and E. 46 These features provide a biochemical basis for interactions between apolipoproteins, including apolipoprotein E, and cubilin as part of a physiologic process that is likely to be relevant to the neurodegeneration/repair that occurs in AD.…”

“…46,47 This endocytic process resembles that for low-density lipoproteins (LDL) and appears to involve the participation of the co-receptor megalin, a member of the LDL receptor family. [46][47][48] Moreover, cubilinmediated HDL endocytosis is inhabitable by apolipoproteins including A-I, A-II, and E. 46 These features provide a biochemical basis for interactions between apolipoproteins, including apolipoprotein E, and cubilin as part of a physiologic process that is likely to be relevant to the neurodegeneration/repair that occurs in AD. Finally, glycogen synthase kinase 3B phosphorylates tau and may contribute to the formation of neurofibrillary tangles in AD through a process that is facilitated by the binding of both proteins to presenilin 1.…”

Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia

“…The present study was initiated to identify ligands to cubilin, the 460-kDa receptor known to function as the intrinsic factorvitamin B 12 ) receptor in the intestine (11,12) and in kidney and yolk sac as the high-affinity apolipoprotein-A1͞HDL receptor (13,14) and low-affinity albumin receptor (15). Cubilin lacks a classical transmembrane region, and the membrane trafficking of cubilin is suggested to be assisted by megalin (16), which colocalizes with and binds to cubilin (11).…”

Cubiline : rôle physiopathologique et relations avec la mégaline

“…L'internalisation de ces complexes fait intervenir au moins un co-récepteur, la mégaline. Cette conclusion repose sur l'interaction démontrée entre cubiline et mégaline et la co-localisation étroite des deux récepteurs [6], l'effet inhibiteur des anticorps anti-mégaline sur l'internalisation de la plupart des ligands, et l'absence d'internalisation des complexes ligand-cubiline chez les souris mégaline -/- [13][14][15][16]. Le rôle physiologique de la cubiline varie en fonction du site d'expression considéré.…”

“…Les ligands sont transférés vers les prélysosomes (PreLYS), puis les lysosomes (LYS) où ils sont dégradés. Lorsque le ligand de la cubiline est lui-même un complexe entre une protéine de [13]. Le mécanisme d'endocytose des lipides par la cubiline, distinct de l'internalisation sélective du cholestérol par le scavenger receptor B I, se rapproche donc du mécanisme décrit par Brown et Goldstein pour les LDL (low densitiy lipoprotein).…”