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

Ramachandran, Haribaskar; Herfurth, Konstantin; Grosschedl, R.; Schäfer, Tobias; Walz, Gerd

doi:doi: 10.1371/journal.pone.0130275

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

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Grosschedl, R.
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Ramachandran, H., Herfurth, K., Grosschedl, R., Schäfer, T., & Walz, G. (2015). SUMOylation Blocks the Ubiquitin-Mediated Degradatoin of the Nephronophthisis Gene Product Glis2/NPHP7. Plos One, 10, e0130275. doi:doi: 10.1371/journal.pone.0130275.

Cite as: https://hdl.handle.net/someHandle/test/escidoc:902582

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.