ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity.

[benign recurrent intrahepatic cholestasis]

Mutations in ATP 8 B 1 cause progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 . Previously , we have shown in mice that Atp 8 b 1 deficiency leads to enhanced biliary excretion of phosphatidylserine , and we hypothesized that ATP 8 B 1 is a flippase for phosphatidylserine . However , direct evidence for this function is still lacking . In Saccharomyces cerevisiae , members of the Cdc 50 p /Lem 3 p family are essential for proper function of the ATP 8 B 1 homologs . We have studied the role of two human members of this family , CDC 50 A and CDC 50 B , in the routing and activity of ATP 8 B 1 . When only ATP 8 B 1 was expressed in Chinese hamster ovary cells , the protein localized to the endoplasmic reticulum . Coexpression with CDC 50 proteins resulted in relocalization of ATP 8 B 1 from the endoplasmic reticulum to the plasma membrane . Only when ATP 8 B 1 was coexpressed with CDC 50 proteins was a 250 %-500 % increase in the translocation of fluorescently labeled phosphatidylserine observed . Importantly , natural phosphatidylserine exposure in the outer leaflet of the plasma membrane was reduced by 17 %-25 % in cells coexpressing ATP 8 B 1 and CDC 50 proteins in comparison with cells expressing ATP 8 B 1 alone . The coexpression of ATP 8 B 1 and CDC 50 A in WIF-B 9 cells resulted in colocalization of both proteins in the canalicular membrane .O ur data indicate that CDC 50 proteins are pivotal factors in the trafficking of ATP 8 B 1 to the plasma membrane and thus may be essential determinants of ATP 8 B 1 -related disease . In the plasma membrane , ATP 8 B 1 functions as a flippase for phosphatidylserine . Finally , CDC 50 A may be the potential beta -subunit or chaperone for ATP 8 B 1 in hepatocytes .

Diseases
Validation

Diseases presenting "atp8b1 deficiency" symptom

benign recurrent intrahepatic cholestasis

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