SUMOylation regulates a variety of cellular processes, including control of transcriptional activities of nuclear receptors. Here, we present SUMOylation of orphan nuclear receptor, ROR alpha by both SUMO-1 and SUMO-2. SUMOylation of RORa occurred on the 240th lysine residue at the hinge region of human protein. PIAS family members, PIASx alpha, PIAS3, and PIASy, increased SUMOylation of ROR alpha, whereas SENP2 specifically removed SUMO from ROR alpha SUMOylation-defective mutant form of ROR alpha exhibited decreased transcriptional activity on ROR alpha-responsive promoters indicating that SUMOylation may positively regulate transcriptional function of ROR alpha. (C) 2008 Elsevier Inc. All rights reserved.