Cubilin, the endocytic receptor for intrinsic factor-vitamin B ₁₂ complex, mediates high-density lipoprotein holoparticle endocytosis

Abstract

Receptors that endocytose high-density lipoproteins (HDL) have been elusive. Here yolk-sac endodermlike cells were used to identify an endocytic receptor for HDL. The receptor was isolated by HDL affinity chromatography and identified as cubilin, the recently described endocytic receptor for intrinsic factor-vitamin B 12 . Cubilin antibodies inhibit HDL endocytosis by the endoderm-like cells and in mouse embryo yolk-sac endoderm, a prominent site of cubilin expression. Cubilin-mediated HDL endocytosis is inhibitable by HDL 2 , HDL 3 , apolipoprotein (apo)A-I, apoA-II, apoE, and RAP, but not by low-density lipoprotein (LDL), oxidized LDL, VLDL, apoC-I, apoC-III, or heparin. These findings, coupled with the fact that cubilin is expressed in kidney proximal tubules, suggest a role for this receptor in embryonic acquisition of maternal HDL and renal catabolism of filterable forms of HDL.

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

“…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). Furthermore, the two receptors act in concert for ligand uptake (13)(14)(15)17).…”

“…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).…”

Co‐expression and interaction of cubilin and megalin in the adult male rat reproductive system

“…While megalin is a typical endocytic receptor with a transmembrane domain and three consensus cytoplasmîc motifs for binding adaptor proteins and clathrin, cubilin is membrane-associated but lacks a transmembrane domain and its intemalization is accomplished by backpacking on megalin (Saïto et al, 1994;Moestrup et al, 1998). Severallines of in vitro evidence, induding cell culture and indirect analyses ofknock out animaIs, have been used to suggest that megalin and cubilin interact functionally in vivo (Burmeister et al, 2001;Kozyraki et al, 2001;Hammad et al, 2000;Nykjaer et al, 2001;Zhai et al, 2000;Hammad et al, 1999).…”