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

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

Author information

1
Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
2
Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, D-79108 Freiburg, Germany.
3
Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany; BIOSS Center for Biological Signaling Studies, 79108 Freiburg, Germany.

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.

PMID:
26083374
PMCID:
PMC4471195
DOI:
10.1371/journal.pone.0130275
[Indexed for MEDLINE]
Free PMC Article

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