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MAGED2 controls vasopressin-induced aquaporin-2 expression in collecting duct cells

Item Type:Article
Title:MAGED2 controls vasopressin-induced aquaporin-2 expression in collecting duct cells
Creators Name:Reusch, B. and Bartram, M.P. and Dafinger, C. and Palacio-Escat, N. and Wenzel, A. and Fenton, R.A. and Saez-Rodriguez, J. and Schermer, B. and Benzing, T. and Altmüller, J. and Beck, B.B. and Rinschen, M.M.
Abstract:Mutations in the Melanoma-Associated Antigen D2 (MAGED2) cause antenatal Bartter syndrome type 5 (BARTS5). This rare disease is characterized by perinatal loss of urinary concentration capability and large urine volumes. The underlying molecular mechanisms of this disease are largely unclear. Here, we study the effect of MAGED2 knockdown on kidney cell cultures using proteomic and phosphoproteomic analyses. In HEK293T cells, MAGED2 knockdown induces prominent changes in protein phosphorylation rather than changes in protein abundance. MAGED2 is expressed in mouse embryonic kidneys and its expression declines during development. MAGED2 interacts with G-protein alpha subunit (GNAS), suggesting a role in G-protein coupled receptors (GPCR) signalling. In kidney collecting duct cell lines, Maged2 knockdown subtly modulated vasopressin type 2 receptor (V2R)-induced cAMP-generation kinetics, rewired phosphorylation-dependent signalling, and phosphorylation of CREB. Maged2 knockdown resulted in a large increase in aquaporin-2 abundance during long-term V2R activation. The increase in aquaporin-2 protein was mediated transcriptionally. Taken together, we link MAGED2 function to cellular signalling as a desensitizer of V2R-induced aquaporin-2 expression. SIGNIFICANCE: In most forms of Bartter Syndrome, the underlying cause of the disease is well understood. In contrast, the role of MAGED2 mutations in a newly discovered form of Bartter Syndrome (BARTS5) is unknown. In our manuscript we could show that MAGED2 modulates vasopressin-induced protein and phosphorylation patterns in kidney cells, providing a broad basis for further studies of MAGED2 function in development and disease.
Keywords:Aquaporin 2, Collecting Kidney Tubules, HEK293 Cells, Neoplasm Antigens, Pregnancy, Proteomics, Signal Transducing Adaptor Proteins, Vasopressins, Animals, Mice
Source:Journal of Proteomics
ISSN:1874-3919
Publisher:Elsevier
Volume:252
Page Range:104424
Date:10 February 2022
Official Publication:https://doi.org/10.1016/j.jprot.2021.104424
PubMed:View item in PubMed

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