O-GlcNAcylation Suppresses the Ion Current IClswell by Preventing the Binding of the Protein ICln to α-Integrin

Frontiers in Cell and Developmental Biology

Angela Marino¹  Rossana Morabito¹  Alessia Remigante¹  Attila Miseta²  Tamás Nagy²  Zoltán Szabó³  Tamás Janáky³  Markus Paulmichl⁴  Antonio Sarikas⁵  Roberta Costa⁵  Emanuele Bernardinelli⁵  Wolfgang Patsch⁵  Silvia Dossena⁵  Davide A. Civello⁵ 

[1] Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy;Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary;Department of Medical Chemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary;Department of Personalized Medicine, Humanomed, Klagenfurt, Austria;Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria;

关键词: O-GlcNAcylation;    IClswell;    ICln;    α-integrin;    regulatory volume decrease;    kidney;   

DOI  :  10.3389/fcell.2020.607080

来源: DOAJ

【 摘 要 】

O-GlcNAcylation is a post-translational modification of proteins that controls a variety of cellular processes, is chronically elevated in diabetes mellitus, and may contribute to the progression of diabetic complications, including diabetic nephropathy. Our previous work showed that increases in the O-GlcNAcylation of cellular proteins impair the homeostatic reaction of the regulatory volume decrease (RVD) after cell swelling by an unknown mechanism. The activation of the swelling-induced chloride current IClswell is a key step in RVD, and ICln, a ubiquitous protein involved in the activation of IClswell, is O-GlcNAcylated. Here, we show that experimentally increased O-GlcNAcylation of cellular proteins inhibited the endogenous as well as the ICln-induced IClswell current and prevented RVD in a human renal cell line, while decreases in O-GlcNAcylation augmented the current magnitude. In parallel, increases or decreases in O-GlcNAcylation, respectively, weakened or stabilized the binding of ICln to the intracellular domain of α-integrin, a process that is essential for the activation of IClswell. Mutation of the putative YinOYang site at Ser67 rendered the ICln-induced IClswell current unresponsive to O-GlcNAc variations, and the ICln interaction with α-integrin insensitive to O-GlcNAcylation. In addition, exposure of cells to a hypotonic solution reduced the O-GlcNAcylation of cellular proteins. Together, these findings show that O-GlcNAcylation affects RVD by influencing IClswell and further indicate that hypotonicity may activate IClswell by reducing the O-GlcNAcylation of ICln at Ser67, therefore permitting its binding to α-integrin. We propose that disturbances in the regulation of cellular volume may contribute to disease in settings of chronically elevated O-GlcNAcylation, including diabetic nephropathy.

【 授权许可】

Unknown