Regulation of Nuclear Receptor Activity by a Pseudouridine Synthase through Posttranscriptional Modification of Steroid Receptor RNA Activator

• Published in: Molecular cell 2004-08, Vol.15 (4), p.549-558
• Main Authors: Zhao, Xiansi, Patton, Jeffrey R., Davis, Shannon L., Florence, Brian, Ames, Sarah J., Spanjaard, Remco A.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Humans; Hydro-Lyases - genetics; Hydro-Lyases - metabolism; Macromolecular Substances; Mice; Promoter Regions, Genetic; Protein Binding; Protein Structure, Tertiary; Pseudouridine - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Retinoic Acid Receptor gamma; RNA Processing, Post-Transcriptional; RNA, Long Noncoding; RNA, Untranslated - metabolism; Signal Transduction - physiology; Transcription, Genetic; Transcriptional Activation; Two-Hybrid System Techniques
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2004.06.044

Nuclear receptors (NRs) induce transcription through association with coactivator complexes. We identified a pseudouridine synthase (PUS), mPus1p, as a coactivator for retinoic acid receptor (mRAR)γ and other NR-dependent transactivation. mPus1p is a member of the truA subfamily of PUSs, a class of enzymes that isomerize uridine to pseudouridine in noncoding RNAs, such as tRNA, to ensure proper folding and function. mPus1p binds the first zinc finger of mRARγ and also associates with other NRs. Interestingly, mPus1p pseudouridylates coactivator Steroid Receptor RNA Activator (SRA), and when coexpressed, mPus1p and SRA cooperatively enhance mRARγ-mediated transcription. mPus1p, mRARγ, and SRA exist in a retinoid-independent, promoter bound complex in the nucleus although mPus1p is also expressed in the nucleolus, where it likely modifies tRNA. Finally, we show that mPus1p-coactivator function required SRA, mPus1p-associated mRARγ binding, and PUS activities. mPus1p-dependent pseudouridylation of SRA represents an additional type of posttranscriptional modification of a NR-coactivator complex that is important for NR signaling.