title: SUMOylation Blocks the Ubiquitin-Mediated Degradation of the Nephronophthisis Gene Product Glis2/NPHP7.
abstract: Glis2/NPHP7 is a transcriptional regulator mutated in type 7 nephronophthisis, an autosomal recessive ciliopathy associated with cystic and fibrotic kidney disease as well as characteristic extrarenal manifestations. While most ciliopathy-associated molecules are found in the cilium, Glis2/NPHP7 presumably localizes to the nucleus. However, the detection of endogenous Glis2/NPHP7 has remained unsuccessful, potentially due to its ubiquitylation-dependent rapid degradation. We report now that Glis2/NPHP7 is also SUMOylated, preferentially by PIAS4, which conjugates Glis2/NPHP7 to SUMO3. SUMOylation interferes with ubiquitylation and degradation of Glis2/NPHP7, suggesting that Glis2/NPHP7 protein levels are regulated by competing ubiquitylation/ SUMOylation. SUMOylation also alters the transcriptional activity of Glis2/NPHP7. While Glis2/NPHP7 activates the mouse insulin-2-promotor (mIns2), SUMOylated Glis2/NPHP7 lacks this property, and seems to act as a repressor. Taken together, our data reveal that Glis2/NPHP7 is extensively modified by post-translational modifications, suggesting that a tight control of this transcriptional regulator is required for normal development and tissue homeostasis.
authors.affiliation: Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Haribaskar
authors.initials: H
authors.lastname: Ramachandran
authors.affiliation: Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Herfurth
authors.affiliation: Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, D-79108 Freiburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.affiliation: Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schäfer
authors.affiliation: Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany; BIOSS Center for Biological Signaling Studies, 79108 Freiburg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D058207:Sumoylation; D025801:Ubiquitin / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C447919:GLIS2 protein, human; D051741:Kruppel-Like Transcription Factors; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; C492189:SUMO3 protein, human; D025801:Ubiquitin; D014452:Ubiquitins