Doherty, D

Furmick, J

Jena, S

Jurutka, PW

Lee, WP

Lemau, J

Schimdt, J

Thompson, PD

Ventakesh, J

Widener, T

PubMed

Wai-Ping Lee

Sarita Jena

Declan Doherty

Jaganathan Ventakesh

Joachim Schimdt

Julie Furmick

Tim Widener

Jana Lemau

Peter W. Jurutka

Paul D. Thompson

Crossref

PLoS ONE

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

HKU Scholars Hub

Sentrin/sumo Specific Proteases As Novel Tissue-selective Modulators Of Vitamin D Receptor-mediated Signaling

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

Peter W Jurutka

Paul D Thompson

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

Sentrin/sumo Specific Proteases As Novel Tissue-selective Modulators Of Vitamin D Receptor-mediated Signaling

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Crossref

HKU Scholars Hub

Directory of Open Access Journals