Negative Modulation of RXRα Transcriptional Activity by Small Ubiquitin-related Modifier (SUMO) Modification and Its Reversal by SUMO-specific Protease SUSP1

Retinoid X receptor α (RXRα) belongs to a family of ligand-activated transcription factors that regulate many aspects of metazoan life. Here we demonstrate that RXRα is a target substrate of a small ubiquitin-related modifier (SUMO)-specific protease, SUSP1, which is capable of controlling the transcriptional activity of RXRα. RXRα was modified by SUMO-1 in vivo as well as in vitro , and the Lys-108 residue within the IKPP sequence of RXRα AF-1 domain was identified as the major SUMO-1 acceptor site. Prevention of SUMO modification by Lys-to-Arg mutation led to an increase not only in the transcriptional activity of RXRα but also in the activity of its heterodimeric complex with retinoic acid receptor-α or peroxisome proliferator-activated receptor-γ (PPARγ). SUSP1 co-localized with RXRα in the nucleus and removed SUMO-1 from RXRα but not from androgen receptor or PPARγ. Moreover, overexpression of SUSP1 caused an increase in the transcriptional activity of RXRα, whereas small hairpin RNA-mediated knockdown of endogenous SUSP1 led to a decrease in RXRα activity. These results suggest that SUSP1 plays an important role in the control of the transcriptional activity of RXRα and thus in the RXRα-mediated cellular processes.