Down-regulation of Na+/H+ Exchanger Regulatory Factor 1 Increases Expression and Function of Multidrug Resistance Protein 4

Multidrug resistance protein 4 (MRP4; ABCC4) is a member of the ATP-binding cassette superfamily of membrane transport proteins and confers resistance to nucleoside and nucleotide analogues as well as camptothecin derivatives. MRP4 also mediates the transmembrane transport of several eicosanoids, conjugated estrogens, and cyclic AMP. The subcellular localization of MRP4 depends on the cell type in which it is expressed, but the molecular determinants responsible for trafficking of MRP4 to the plasma membrane are unknown. Here, we describe the interaction of Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) with MRP4 via the last four amino acids ((1322)ETAL(1325)) of the transporter. Down-regulation of NHERF1 by small interfering RNA (siRNA) in HeLa cells significantly increased MRP4 levels at the plasma membrane, suggesting that…