{"publication":"Journal of Biological Chemistry","abstract":[{"text":"Inactivation of the mainly endosomal 2Cl-/H+- exchanger ClC-5 severely impairs endocytosis in renal proximal tubules and underlies the human kidney stone disorder Dent's disease. In heterologous expression systems, interaction of the E3 ubiquitin ligasesWWP2and Nedd4-2 with a &quot;PY-motif&quot; in the cytoplasmic C terminus of ClC-5 stimulates its internalization from the plasma membrane and may influence receptor-mediated endocytosis. We asked whether this interaction is relevant in vivo and generated mice in which the PY-motif was destroyed by a point mutation. Unlike ClC-5 knock-out mice, these knock-in mice displayed neither low molecular weight proteinuria nor hyperphosphaturia, and both receptor-mediated and fluid-phase endocytosis were normal. The abundances and localizations of the endocytic receptor megalin and of the Na+-coupled phosphate transporter NaPi-2a (Npt2) were not changed, either. To explore whether the discrepancy in results from heterologous expression studies might be due to heteromerization of ClC-5 with ClC-3 or ClC-4 in vivo, we studied knock-in mice additionally deleted for those related transporters. Disruption of neither ClC-3 nor ClC-4 led to proteinuria or impaired proximal tubular endocytosis by itself, nor in combination with the PY-mutant of ClC-5. Endocytosis of cells lacking ClC-5 was not impaired further when ClC-3 or ClC-4 was additionally deleted. We conclude that ClC-5 is unique among CLC proteins in being crucial for proximal tubular endocytosis and that PY-motif-dependent ubiquitylation of ClC-5 is dispensable for this role.","lang":"eng"}],"volume":285,"date_updated":"2021-01-12T06:56:42Z","day":"04","quality_controlled":0,"page":"17595 - 17603","date_created":"2018-12-11T11:56:55Z","title":"Role of ClC-5 in renal endocytosis is unique among ClC exchangers and does not require PY-motif-dependent ubiquitylation","_id":"2311","month":"06","type":"journal_article","date_published":"2010-06-04T00:00:00Z","issue":"23","citation":{"apa":"Rickheit, G., Wartosch, L., Schaffer, S., Stobrawa, S., Novarino, G., Weinert, S., &#38; Jentsch, T. (2010). Role of ClC-5 in renal endocytosis is unique among ClC exchangers and does not require PY-motif-dependent ubiquitylation. <i>Journal of Biological Chemistry</i>. American Society for Biochemistry and Molecular Biology. <a href=\"https://doi.org/10.1074/jbc.M110.115600\">https://doi.org/10.1074/jbc.M110.115600</a>","mla":"Rickheit, Gesa, et al. “Role of ClC-5 in Renal Endocytosis Is Unique among ClC Exchangers and Does Not Require PY-Motif-Dependent Ubiquitylation.” <i>Journal of Biological Chemistry</i>, vol. 285, no. 23, American Society for Biochemistry and Molecular Biology, 2010, pp. 17595–603, doi:<a href=\"https://doi.org/10.1074/jbc.M110.115600\">10.1074/jbc.M110.115600</a>.","ieee":"G. Rickheit <i>et al.</i>, “Role of ClC-5 in renal endocytosis is unique among ClC exchangers and does not require PY-motif-dependent ubiquitylation,” <i>Journal of Biological Chemistry</i>, vol. 285, no. 23. American Society for Biochemistry and Molecular Biology, pp. 17595–17603, 2010.","ista":"Rickheit G, Wartosch L, Schaffer S, Stobrawa S, Novarino G, Weinert S, Jentsch T. 2010. Role of ClC-5 in renal endocytosis is unique among ClC exchangers and does not require PY-motif-dependent ubiquitylation. Journal of Biological Chemistry. 285(23), 17595–17603.","chicago":"Rickheit, Gesa, Lena Wartosch, Sven Schaffer, Sandra Stobrawa, Gaia Novarino, Stefanie Weinert, and Thomas Jentsch. “Role of ClC-5 in Renal Endocytosis Is Unique among ClC Exchangers and Does Not Require PY-Motif-Dependent Ubiquitylation.” <i>Journal of Biological Chemistry</i>. American Society for Biochemistry and Molecular Biology, 2010. <a href=\"https://doi.org/10.1074/jbc.M110.115600\">https://doi.org/10.1074/jbc.M110.115600</a>.","ama":"Rickheit G, Wartosch L, Schaffer S, et al. Role of ClC-5 in renal endocytosis is unique among ClC exchangers and does not require PY-motif-dependent ubiquitylation. <i>Journal of Biological Chemistry</i>. 2010;285(23):17595-17603. doi:<a href=\"https://doi.org/10.1074/jbc.M110.115600\">10.1074/jbc.M110.115600</a>","short":"G. Rickheit, L. Wartosch, S. Schaffer, S. Stobrawa, G. Novarino, S. Weinert, T. Jentsch, Journal of Biological Chemistry 285 (2010) 17595–17603."},"publication_status":"published","author":[{"first_name":"Gesa","last_name":"Rickheit","full_name":"Rickheit, Gesa"},{"full_name":"Wartosch, Lena","last_name":"Wartosch","first_name":"Lena"},{"last_name":"Schaffer","first_name":"Sven","full_name":"Schaffer, Sven"},{"first_name":"Sandra","last_name":"Stobrawa","full_name":"Stobrawa, Sandra M"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Gaia Novarino","first_name":"Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178"},{"first_name":"Stefanie","last_name":"Weinert","full_name":"Weinert, Stefanie"},{"full_name":"Jentsch, Thomas J","first_name":"Thomas","last_name":"Jentsch"}],"status":"public","publist_id":"4618","year":"2010","extern":1,"publisher":"American Society for Biochemistry and Molecular Biology","doi":"10.1074/jbc.M110.115600","intvolume":"       285"}