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10.1074/jbc.M115.702514 http://scihub22266oqcxt.onion/10.1074/jbc.M115.702514 26721884!4813476!26721884     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26721884&cmd=llinks): Failed to open stream: HTTP request failed! 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OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets Its Immature Form for the Endoplasmic Reticulum-associated Degradation Pathway |pdf=|usr=}}{{26721884}} gab.com Text OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets Its Immature Form for the Endoplasmic Reticulum-associated Degradation Pathway JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=26721884 #FOAvip Mutations in the renal specific Na-K-2Cl co-transporter (NKCC2) lead to type I Bartter syndrome, a life-threatening kidney disease featuring arterial hypotension along with electrolyte abnormalities. We have previously shown that NKCC2 and its disease-causing mutants are subject to regulation by endoplasmic reticulum-associated degradation (ERAD). The aim of the present study was to identify the protein partners specifically involved in ERAD of NKCC2. To this end, we screened a kidney cDNA library through a yeast two-hybrid assay using NKCC2 C terminus as bait. We identified OS9 (amplified in osteosarcomas) as a novel and specific binding partner of NKCC2. Co-immunoprecipitation assays in renal cells revealed that OS9 association involves mainly the immature form of NKCC2. Accordingly, immunocytochemistry analysis showed that NKCC2 and OS9 co-localize at the endoplasmic reticulum. In cells overexpressing OS9, total cellular NKCC2 protein levels were markedly decreased, an effect blocked by the proteasome inhibitor MG132. Pulse-chase and cycloheximide-chase assays demonstrated that the marked reduction in the co-transporter protein levels was essentially due to increased protein degradation of the immature form of NKCC2. Conversely, knockdown of OS9 by small interfering RNA increased NKCC2 expression by increasing the co-transporter stability. Inactivation of the mannose 6-phosphate receptor homology domain of OS9 had no effect on its action on NKCC2. In contrast, mutations of NKCC2 N-glycosylation sites abolished the effects of OS9, indicating that OS9-induced protein degradation is N-glycan-dependent. In summary, our results demonstrate the presence of an OS9-mediated ERAD pathway in renal cells that degrades immature NKCC2 proteins. The identification and selective modulation of ERAD components specific to NKCC2 and its disease-causing mutants might provide novel therapeutic strategies for the treatment of type I Bartter syndrome. Twit Text FOAVip OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets Its Immature Form for the Endoplasmic Reticulum-associated Degradation Pathway ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=26721884 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26721884 #FOAvip English Wikipedia <ref>{{Cite pmid|26721884}}</ref> OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets Its Immature Form for the Endoplasmic Reticulum-associated Degradation Pathway #MMPMID26721884 Seaayfan E; Defontaine N; Demaretz S; Zaarour N; Laghmani K J Biol Chem 2016[Feb]; 291 (9): 4487-502 PMID26721884show ga Mutations in the renal specific Na-K-2Cl co-transporter (NKCC2) lead to type I Bartter syndrome, a life-threatening kidney disease featuring arterial hypotension along with electrolyte abnormalities. We have previously shown that NKCC2 and its disease-causing mutants are subject to regulation by endoplasmic reticulum-associated degradation (ERAD). The aim of the present study was to identify the protein partners specifically involved in ERAD of NKCC2. To this end, we screened a kidney cDNA library through a yeast two-hybrid assay using NKCC2 C terminus as bait. We identified OS9 (amplified in osteosarcomas) as a novel and specific binding partner of NKCC2. Co-immunoprecipitation assays in renal cells revealed that OS9 association involves mainly the immature form of NKCC2. Accordingly, immunocytochemistry analysis showed that NKCC2 and OS9 co-localize at the endoplasmic reticulum. In cells overexpressing OS9, total cellular NKCC2 protein levels were markedly decreased, an effect blocked by the proteasome inhibitor MG132. Pulse-chase and cycloheximide-chase assays demonstrated that the marked reduction in the co-transporter protein levels was essentially due to increased protein degradation of the immature form of NKCC2. Conversely, knockdown of OS9 by small interfering RNA increased NKCC2 expression by increasing the co-transporter stability. Inactivation of the mannose 6-phosphate receptor homology domain of OS9 had no effect on its action on NKCC2. In contrast, mutations of NKCC2 N-glycosylation sites abolished the effects of OS9, indicating that OS9-induced protein degradation is N-glycan-dependent. In summary, our results demonstrate the presence of an OS9-mediated ERAD pathway in renal cells that degrades immature NKCC2 proteins. The identification and selective modulation of ERAD components specific to NKCC2 and its disease-causing mutants might provide novel therapeutic strategies for the treatment of type I Bartter syndrome. |*Endoplasmic Reticulum-Associated Degradation/drug effects[MESH] |Amino Acid Substitution[MESH] |Animals[MESH] |Bartter Syndrome/genetics/metabolism[MESH] |Cell Line[MESH] |Gene Library[MESH] |Glycosylation/drug effects[MESH] |HEK293 Cells[MESH] |Humans[MESH] |Immunoprecipitation[MESH] |Kidney/drug effects/*metabolism[MESH] |Lectins/antagonists & inhibitors/chemistry/genetics/*metabolism[MESH] |Mutation[MESH] |Neoplasm Proteins/antagonists & inhibitors/chemistry/genetics/*metabolism[MESH] |Opossums[MESH] |Peptide Fragments/chemistry/genetics/metabolism[MESH] |Proteasome Inhibitors/pharmacology[MESH] |Protein Processing, Post-Translational/drug effects[MESH] |Protein Stability/drug effects[MESH] |Protein Structure, Tertiary[MESH] |RNA Interference[MESH] |Recombinant Fusion Proteins/chemistry/metabolism[MESH]OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets(epmc).pdf DeepDyve Pubget Overpricing