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 W 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 (RXRα) 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
Pages (from-to)e89506
JournalPLoS ONE
Volume9
Issue number2
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Animals
  • Blotting, Western
  • CHO Cells
  • Cricetulus
  • Cysteine Endopeptidases/genetics
  • Endopeptidases/genetics
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Mutagenesis, Site-Directed
  • Mutation/genetics
  • RNA, Messenger/genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Calcitriol/genetics
  • Retinoid X Receptors/genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Small Ubiquitin-Related Modifier Proteins/genetics
  • Transcription, Genetic

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