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

Grants and funding

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.