2. Academic Validation
  3. UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability

UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability

  • Mol Cell. 2023 Aug 3;83(15):2753-2767.e10. doi: 10.1016/j.molcel.2023.06.028.
Jonathan M Tsai 1,  Jacob D Aguirre 2,  Yen-Der Li 3,  Jared Brown 4,  Vivian Focht 2,  Lukas Kater 2,  Georg Kempf 2,  Brittany Sandoval 5,  Stefan Schmitt 2,  Justine C Rutter 5,  Pius Galli 6,  Colby R Sandate 2,  Jevon A Cutler 7,  Charles Zou 5,  Katherine A Donovan 8,  Ryan J Lumpkin 8,  Simone Cavadini 2,  Paul M C Park 5,  Quinlan Sievers 5,  Charlie Hatton 7,  Elizabeth Ener 7,  Brandon D Regalado 7,  Micah T Sperling 9,  Mikołaj Słabicki 5,  Jeonghyeon Kim 8,  Rebecca Zon 9,  Zinan Zhang 9,  Peter G Miller 10,  Roger Belizaire 11,  Adam S Sperling 12,  Eric S Fischer 8,  Rafael Irizarry 4,  Scott A Armstrong 7,  Nicolas H Thomä 13,  Benjamin L Ebert 14
Affiliations

Affiliations

  • 1 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 2 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 3 Division of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Molecular & Cellular Biology, Harvard University, Cambridge, MA, USA.
  • 4 Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 5 Division of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 6 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Faculty of Science, University of Basel, Basel, Switzerland.
  • 7 Pediatric Hematology-Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 8 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 9 Division of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 10 Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • 11 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 12 Division of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 13 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Electronic address: nicolas.thoma@fmi.ch.
  • 14 Division of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA. Electronic address: benjamin_ebert@dfci.harvard.edu.
PMID: 37478846 DOI: 10.1016/j.molcel.2023.06.028
Abstract

Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin Ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin Ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective Estrogen Receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.

Keywords

HECT-E3 ligases; nuclear receptors; protein degradation; structural biology; ubiquitin ligases.

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