Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin.
Cobalamin (Cbl, vitamin B(12)) deficiency in humans is a cause of hematologic and neurologic disorders. We show here that the cellular export of Cbl, in contrast to the carrier- and receptor-dependent cellular import of Cbl, occurs by transmembrane transport of "free" Cbl. Screening of candidate transporters by cellular gene silencing showed a role in cellular Cbl efflux of the ATP-binding cassette (ABC)-drug transporter, ABCC1, alias multidrug resistance protein 1 (MRP1), which is present in the basolateral membrane of intestinal epithelium and in other cells. The ability of MRP1 to mediate ATP-dependent Cbl transport was confirmed by vesicular transport experiments, and a physiologic role of MRP1 in mammalian Cbl homeostasis is indicated by the phenotype of knockout mice with targeted disruption of MRP1. These animals have a reduced concentration of Cbl in plasma and in the storage organs liver and kidney. In contrast, Cbl accumulates in the terminal part of the intestine of these mice, suggesting a functional malabsorption because of a lower epithelial basolateral Cbl efflux. The identification of this Cbl export mechanism now allows the delineation of a coherent pathway for Cbl trafficking from food to the body cells.
Beedholm-Ebsen
Rasmus
R
Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
van de Wetering
Koen
K
Hardlei
Tore
T
Nexø
Ebba
E
Borst
Piet
P
Moestrup
Søren K
SK
D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014805:Vitamin B 12 / Q000235:genetics / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000235:genetics / Q000378:metabolism
D000255:Adenosine Triphosphate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014805:Vitamin B 12; C421109:multidrug resistance-associated protein 1