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Missorting of the Aquaporin-2 mutant E258K to multivesicular bodies/lysosomes in dominant NDI is associated with its monoubiquitination and increased phosphorylation by PKC but is due to the loss of E258

  • Cell and Molecular Physiology
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Abstract

To stimulate renal water reabsorption, vasopressin induces phosphorylation of Aquaporin-2 (AQP2) water channels at S256 and their redistribution from vesicles to the apical membrane, whereas vasopressin removal results in AQP2 ubiquitination at K270 and its internalization to multivesicular bodies (MVB). AQP2-E258K causes dominant nephrogenic diabetes insipidus (NDI), but its subcellular location is unclear, and the molecular reason for its involvement in dominant NDI is unknown. To unravel these, AQP2-E258K was studied in transfected polarized Madin–Darby canine kidney (MDCK) cells. In MDCK cells, AQP2-E258K mainly localized to MVB/lysosomes (Lys). Upon coexpression, wild-type (wt) AQP2 and AQP2-E258K formed multimers, which also localized to MVB/Lys, independent of forskolin stimulation. Orthophosphate labeling revealed that forskolin increased phosphorylation of wt-AQP2 and AQP2-E258K but not AQP2-S256A, indicating that the E258K mutation does not interfere with the AQP2 phosphorylation at S256. In contrast to wt-AQP2 but consistent with the introduced protein kinase C (PKC) consensus site, AQP2-E258K was phosphorylated by phorbol esters. Besides the 29-kDa band, however, an additional band of about 35 kDa was observed for AQP2-E258K only, which represented AQP2-E258K uniquely monoubiquitinated at K228 only. Analysis of several mutants interfering with AQP2-E258K phosphorylation, and/or ubiquitination, however, revealed that the MVB/lysosomal sorting of AQP2-E258K occurred independent of its monoubiquitination or phosphorylation by PKC. Instead, our data reveal that the loss of the E258 in AQP2-E258K is fundamental to its missorting to MVB/Lys and indicate that this amino acid has an important role in the proper structure formation of the C-terminal tail of AQP2.

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Acknowledgments

This research was supported by grants from the Dutch Organization of Scientific Research (NWO-MW 902-18-292) to PMTD and PvdS and to EJK (NWO; 916.36.122) and from the European Union (QLRT-2000-00778, QLK3-CT-2001-00987) to PMTD.

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Authors and Affiliations

  1. Department of Physiology, Radboud University Nijmegen Medical Center, Research Tower, 7th floor; UMC St Radboud, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Erik-Jan Kamsteeg, Paul J. M. Savelkoul, Irene B. M. Konings, Nicole M. I. Nivillac, Anne Karine Lagendijk & Peter M. T. Deen

  2. Department of Cell Biology, UMC Utrecht, Utrecht, The Netherlands

    Giel Hendriks & Peter van der Sluijs

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  1. Erik-Jan Kamsteeg
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  2. Paul J. M. Savelkoul
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Correspondence to Peter M. T. Deen.

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Kamsteeg, EJ., Savelkoul, P.J.M., Hendriks, G. et al. Missorting of the Aquaporin-2 mutant E258K to multivesicular bodies/lysosomes in dominant NDI is associated with its monoubiquitination and increased phosphorylation by PKC but is due to the loss of E258. Pflugers Arch - Eur J Physiol 455, 1041–1054 (2008). https://doi.org/10.1007/s00424-007-0364-6

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