SUMOylation Blocks the Ubiquitin-Mediated Degradation of the Nephronophthisis Gene Product Glis2/NPHP7

PLoS One. 2015 Jun 17;10(6):e0130275. doi: 10.1371/journal.pone.0130275. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • HEK293 Cells
  • Humans
  • Kidney Diseases, Cystic / genetics*
  • Kruppel-Like Transcription Factors / chemistry
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mutation
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT / metabolism
  • Protein Stability
  • Proteolysis*
  • Sumoylation*
  • Ubiquitin / metabolism*
  • Ubiquitins / metabolism

Substances

  • GLIS2 protein, human
  • Kruppel-Like Transcription Factors
  • PIAS4 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT
  • SUMO3 protein, human
  • Ubiquitin
  • Ubiquitins

Supplementary concepts

  • Nephronophthisis 7

Grant support

DFG SFB 746 (R.G., T.S. and G.W.) European Community’s Seventh Framework Program (grant agreement number 241955, SSCILIA) (G.W.). The funders had no role in any of the above.