Sentrin/SUMO Specific Proteases as Novel Tissue-Selective Modulators of Vitamin D Receptor-Mediated Signaling

Paul Thompson, Sarita Jena, Declan Doherty, WP Lee, Jaganathan Venkatesh, Schmidt Joachim, Tim Widener, Julie Furmick, Jana Lemau, Peter Jurutka

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7 Citations (Scopus)

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
Article numbere89506
Number of pages12
JournalPLoS ONE
Volume9(2)
DOIs
Publication statusPublished - Feb 2014

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    Thompson, P., Jena, S., Doherty, D., Lee, WP., Venkatesh, J., Joachim, S., Widener, T., Furmick, J., Lemau, J., & Jurutka, P. (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