Sorting Nexin 27 Interacts with Multidrug Resistance-associated Protein 4 (MRP4) and Mediates Internalization of MRP4

Hayashi, Hisamitsu; Naoi, Sotaro; Nakagawa, Takayuki; Nishikawa, Toru; Fukuda, Hiroyuki; Imajoh‐Ohmi, Shinobu; Kondo, Ayano; Kubo, Kiyotaka; Yabuki, Takashi; Hattori, Asami; Hirouchi, Masakazu; Sugiyama, Yuichi

doi:10.1074/jbc.m111.337931

Cited by 35 publications

(35 citation statements)

References 37 publications

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“…Modulation of endosomal retrieval or ubiquitination can regulate the change in the degradation rate of apical-surface-resident ABC transporters, thereby inducing their cell-surface expression and increasing their activity (89)(90)(91)(92).…”

Section: Discussionmentioning

confidence: 99%

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

Masereeuw

Rüssel

2012

AAPS J

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Abstract. The ATP-binding cassette transport proteins (ABC transporters) represent important determinants of drug excretion. Protective or excretory tissues where these transporters mediate substrate efflux include the kidney proximal tubule. Regulation of the transport proteins in this tissue requires elaborate signaling pathways, including genetic, epigenetic, nuclear receptor mediated, posttranscriptional gene regulation involving microRNAs, and non-genomic (kinases) pathways triggered by hormones and/or growth factors. This review discusses current knowledge on regulatory pathways for ABC transporters in kidney proximal tubules, with a main focus on P-glycoprotein, multidrug resistance proteins 2 and 4, and breast cancer resistance protein. Insight in these processes is of importance because variations in transporter activity due to certain (disease) conditions could lead to significant changes in drug efficacy or toxicity.

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Section: Discussionmentioning

confidence: 99%

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

Masereeuw

Rüssel

2012

AAPS J

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“…Previous studies have shown that the PX domain of these proteins binds with high specificity to PtdIns3P, driving their localization to PtdIns3P-enriched early endosomes Stockinger et al, 2002). PX-FERM proteins can then interact with cargo containing NPxY or NxxY motifs, and also PDZ-binding motif (PDZbm) cargo, in the case of SNX27, at the early endosomal membrane (Balana et al, 2011;Bottcher et al, 2012;Cai et al, 2011;Ghai et al, 2013;Hayashi et al, 2012;Joubert et al, 2004;Knauth et al, 2005;Lauffer et al, 2010;Lunn et al, 2007;Steinberg et al, 2013;Temkin et al, 2011;Valdes et al, 2011;Wang et al, 2013). This influences the routing of transmembrane cargo trafficking, away from degradative late endosomes and into recycling and retrieval pathways from the endosome back to the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

“…We and others have found that, upon T-cell activation, SNX27 is sorted into two pools at the immunological synapse, where it is found at both the plasma membrane and on transferrin receptor (TfR)-positive intracellular vesicles thought to be recycling endosomes Rincón et al, 2011;Rincón et al, 2007). In addition, SNX27 was also found in plasma-membrane-enriched membrane fractions in cell surface biotinylation experiments (Hayashi et al, 2012). The mechanism of SNX27 relocalization to the immunological synapse remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide binding by the SNX27 FERM domain regulates localisation at the immune synapse of activated T-cells

Ghai

Tello-Lafoz

Norwood

et al. 2014

Journal of Cell Science

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Sorting nexin 27 (SNX27) controls the endosomal-to-cell-surface recycling of diverse transmembrane protein cargos. Crucial to this function is the recruitment of SNX27 to endosomes which is mediated by the binding of phosphatidylinositol-3-phosphate (PtdIns3P) by its phox homology (PX) domain. In T-cells, SNX27 localizes to the immunological synapse in an activation-dependent manner, but the molecular mechanisms underlying SNX27 translocation remain to be clarified. Here, we examined the phosphoinositide-lipid-binding capabilities of full-length SNX27, and discovered a new PtdInsPbinding site within the C-terminal 4.1, ezrin, radixin, moesin (FERM) domain. This binding site showed a clear preference for bi-and tri-phosphorylated phophoinositides, and the interaction was confirmed through biophysical, mutagenesis and modeling approaches. At the immunological synapse of activated T-cells, cell signaling regulates phosphoinositide dynamics, and we find that perturbing phosphoinositide binding by the SNX27 FERM domain alters the SNX27 distribution in both endosomal recycling compartments and PtdIns(3,4,5)P 3 -enriched domains of the plasma membrane during synapse formation. Our results suggest that SNX27 undergoes dynamic partitioning between different membrane domains during immunological synapse assembly, and underscore the contribution of unique lipid interactions for SNX27 orchestration of cargo trafficking.

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“…16 In addition, sorting nexin 27, a member of the sorting nexin family of proteins known to be involved in the cellular trafficking and sorting of cargo proteins, also binds to cell surface MRP4 and increases its internalization. 26 Therefore, it is possible that NHERF3 expression may inhibit the associations between these internalization-promoting PDZ proteins and MRP4. Especially in cells that express both NHERF1 and NHERF3, such as kidney tubules, ablation of NHERF3 may play a particularly important role in disrupting the balance between the MRP4-NHERF1 and MRP4-NHERF3 associations, increasing the internalization and degradation of MRP4.…”

Section: Discussionmentioning

confidence: 99%

Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4–Mediated Drug Efflux in the Kidney

Park

Kwak

Riederer

et al. 2014

Journal of the American Society of Nephrology

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Na+ /H + exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3 2/2 ) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3 2/2 mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules. Assembly of protein complexes by adaptor proteins with PSD-95/discs large/ZO-1 (PDZ) domains plays an important role in the regulation of many membrane proteins, especially in epithelial and neuronal tissues. 1,2 For example, PDZ-based adapter proteins in epithelia, such as Shank2, synaptic scaffolding molecule (S-SCAM), and Na + /H + exchanger regulatory factors (NHERFs), are known to be involved in the regulation of cell surface expression and the activity of many membrane transporters and receptors in the respiratory, digestive, urinary, and reproductive organs. [3][4][5][6] The four members of the NHERF proteins (NHERF1 to 4) contain either two or four PDZ domains and were the first family of PDZ-containing proteins shown

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Sorting Nexin 27 Interacts with Multidrug Resistance-associated Protein 4 (MRP4) and Mediates Internalization of MRP4

Cited by 35 publications

References 37 publications

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

Phosphoinositide binding by the SNX27 FERM domain regulates localisation at the immune synapse of activated T-cells

Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4–Mediated Drug Efflux in the Kidney

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