Regulation of nuclear receptor activity by a pseudouridine synthase through posttranscriptional modification of steroid receptor RNA activator.
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)gamma 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 mRARgamma and also associates with other NRs. Interestingly, mPus1p pseudouridylates coactivator Steroid Receptor RNA Activator (SRA), and when coexpressed, mPus1p and SRA cooperatively enhance mRARgamma-mediated transcription. mPus1p, mRARgamma, 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 mRARgamma 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.
Department of Otolaryngology, Boston University School of Medicine, Boston, MA 02118, USA.
Xiansi
X
Zhao
Jeffrey R
JR
Patton
Shannon L
SL
Davis
Brian
B
Florence
Sarah J
SJ
Ames
Remco A
RA
Spanjaard
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011560:Pseudouridine / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D000097768:Retinoic Acid Receptor gamma
D006836:Hydro-Lyases; D046911:Macromolecular Substances; D011560:Pseudouridine; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000097768:Retinoic Acid Receptor gamma; C082925:retinoic acid receptor beta; C405423:steroid receptor RNA activator; C022479:pseudouridylate synthetase