这篇论文揭示了Dubin-Johnson综合征中MRP2Δ(R,M)基因突变如何影响蛋白质成熟和细胞膜定位。研究发现，缺失Arg1392和Met1393导致MRP2蛋白在内质网滞留，且对糖基化处理受损。进一步实验表明，蛋白酶体可能参与突变蛋白的降解。这是首次报道的MRP2突变影响其成熟并妨碍糖蛋白正确排到细胞极性的案例。
摘要：
The Dubin-Johnson syndrome is an inherited disorder characterized by conjugated hyperbilirubinemia. The deficient hepatobiliary transport of anionic conjugates is caused by the absence of a functional multidrug-resistance protein 2 (MRP2, symbol ABCC2) from the apical (canalicular) membrane of hepatocytes. Mechanisms underlying this deficiency may include rapid degradation of mutated MRP2 messenger RNA (mRNA) or impaired MRP2 protein maturation and trafficking. We investigated the consequences of the mutation MRP2Δ(R,M), which leads to the loss of 2 amino acids from the second ATP-binding domain of MRP2. The MRP2Δ(R,M) mutation is associated with the absence of the MRP2 glycoprotein from the apical membrane of hepatocytes. Transfection of mutated MRP2 complementary DNA (cDNA) led to an MRP2Δ(R,M) protein that was only core glycosylated, sensitive to endoglycosidase H digestion, and located in the endoplasmic reticulum (ER) of transfected HEK293 and HepG2 cells. This indicated that deletion of Arg1392 and Met1393 leads to impaired maturation and trafficking of the protein from the ER to the Golgi complex. Inhibition of proteasome function resulted in a paranuclear accumulation of the MRP2Δ(R,M) protein, suggesting that proteasomes are involved in the degradation of the mutant protein. This is the first mutation in Dubin-Johnson syndrome shown to cause deficient MRP2 maturation and impaired sorting of this glycoprotein to the apical membrane. (Hepatology2000;32:1317-1328.)
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