Sentrin/SUMO specific proteases as novel tissue-selective modulators of vitamin D receptor-mediated signaling

Wai Ping Lee, Sarita Jena, Declan Doherty, Jaganathan Ventakesh, Joachim Schimdt, Julie Furmick, Tim Widener, Jana Lemau, Peter Jurutka, Paul D. Thompson

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7 Scopus citations

Abstract

Vitamin D receptor (VDR) is a substrate for modification with small ubiquitin-like modifier (SUMO). To further assess the role of reversible SUMOylation within the vitamin D hormonal response, we evaluated the effects of sentrin/SUMO-specific proteases (SENPs) that can function to remove small ubiquitin-like modifier (SUMO) from target proteins upon the activities of VDR and related receptors. We report that SENP1 and SENP2 strikingly potentiate ligand-mediated transactivation of VDR and also its heterodimeric partner, retinoid X receptor (RXRa) with depletion of cellular SENP1 significantly diminishing the hormonal responsiveness of the endogenous vitamin D target gene CYP24A1. We find that SENP-directed modulation of VDR activity is cell line-dependent, achieving potent modulatory effects in Caco-2 and HEK-293 cells, while in MCF-7 cells the vitamin D signal is unaffected by any tested SENP. In support of their function as novel modulators of the vitamin D hormonal pathway we demonstrate that both SENP1 and SENP2 can interact with VDR and reverse its modification with SUMO2. In a preliminary analysis we identify lysine 91, a residue known to be critical for formation and DNA binding of the VDR-RXR heterodimer, as a minor SUMO acceptor site within VDR. In combination, our results support a repressor function for SUMOylation of VDR and reveal SENPs as a novel class of VDR/RXR co-regulatory protein that significantly modulate the vitamin D response and which could also have important impact upon the functionality of both RXR-containing homo and heterodimers.

Original languageEnglish (US)
Article numbere89506
JournalPloS one
Volume9
Issue number2
DOIs
StatePublished - Feb 20 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Lee, W. P., Jena, S., Doherty, D., Ventakesh, J., Schimdt, J., Furmick, J., Widener, T., Lemau, J., Jurutka, P., & Thompson, P. D. (2014). Sentrin/SUMO specific proteases as novel tissue-selective modulators of vitamin D receptor-mediated signaling. PloS one, 9(2), [e89506]. https://doi.org/10.1371/journal.pone.0089506