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

Research output: Contribution to journalArticle

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 (US)
Article numbere89506
JournalPLoS One
Volume9
Issue number2
DOIs
StatePublished - Feb 20 2014

Fingerprint

SUMO-1 Protein
Calcitriol Receptors
modifiers (genes)
ubiquitin
Ubiquitin
vitamin D
Modulators
Peptide Hydrolases
proteinases
Tissue
receptors
Vitamin D
Sumoylation
Retinoid X Receptors
tissues
HEK293 Cells
MCF-7 Cells
Transcriptional Activation
Lysine
Proteins

ASJC Scopus subject areas

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

Cite this

Lee, W. P., Jena, S., Doherty, D., Ventakesh, J., Schimdt, J., Furmick, J., ... 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

Sentrin/SUMO specific proteases as novel tissue-selective modulators of vitamin D receptor-mediated signaling. / Lee, Wai Ping; Jena, Sarita; Doherty, Declan; Ventakesh, Jaganathan; Schimdt, Joachim; Furmick, Julie; Widener, Tim; Lemau, Jana; Jurutka, Peter; Thompson, Paul D.

In: PLoS One, Vol. 9, No. 2, e89506, 20.02.2014.

Research output: Contribution to journalArticle

Lee, WP, Jena, S, Doherty, D, Ventakesh, J, Schimdt, J, Furmick, J, Widener, T, Lemau, J, Jurutka, P & Thompson, PD 2014, 'Sentrin/SUMO specific proteases as novel tissue-selective modulators of vitamin D receptor-mediated signaling', PLoS One, vol. 9, no. 2, e89506. https://doi.org/10.1371/journal.pone.0089506
Lee, Wai Ping ; Jena, Sarita ; Doherty, Declan ; Ventakesh, Jaganathan ; Schimdt, Joachim ; Furmick, Julie ; Widener, Tim ; Lemau, Jana ; Jurutka, Peter ; Thompson, Paul D. / Sentrin/SUMO specific proteases as novel tissue-selective modulators of vitamin D receptor-mediated signaling. In: PLoS One. 2014 ; Vol. 9, No. 2.
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