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

Jonathan M Tsai; Jacob D Aguirre; Yen-Der Li; Jared Brown; Vivian Focht; Lukas Kater; Georg Kempf; Brittany Sandoval; Stefan Schmitt; Justine C Rutter; Pius Galli; Colby R Sandate; Jevon A Cutler; Charles Zou; Katherine A Donovan; Ryan J Lumpkin; Simone Cavadini; Paul M C Park; Quinlan Sievers; Charlie Hatton; Elizabeth Ener; Brandon D Regalado; Micah T Sperling; Mikołaj Słabicki; Jeonghyeon Kim; Rebecca Zon; Zinan Zhang; Peter G Miller; Roger Belizaire; Adam S Sperling; Eric S Fischer; Rafael Irizarry; Scott A Armstrong; Nicolas H Thomä; Benjamin L Ebert

doi:10.1016/j.molcel.2023.06.028

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. Epub 2023 Jul 20.

Authors

Jonathan M Tsai¹, Jacob D Aguirre², Yen-Der Li³, Jared Brown⁴, Vivian Focht², Lukas Kater², Georg Kempf², Brittany Sandoval⁵, Stefan Schmitt², Justine C Rutter⁵, Pius Galli⁶, Colby R Sandate², Jevon A Cutler⁷, Charles Zou⁵, Katherine A Donovan⁸, Ryan J Lumpkin⁸, Simone Cavadini², Paul M C Park⁵, Quinlan Sievers⁵, Charlie Hatton⁷, Elizabeth Ener⁷, Brandon D Regalado⁷, Micah T Sperling⁹, Mikołaj Słabicki⁵, Jeonghyeon Kim⁸, Rebecca Zon⁹, Zinan Zhang⁹, Peter G Miller¹⁰, Roger Belizaire¹¹, Adam S Sperling¹², Eric S Fischer⁸, Rafael Irizarry⁴, Scott A Armstrong⁷, Nicolas H Thomä¹³, Benjamin L Ebert¹⁴

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Chromatin* / genetics
Humans
Ligands
Receptors, Cytoplasmic and Nuclear / genetics
Transcription Factors* / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitins

Substances

Ligands
Chromatin
Transcription Factors
Receptors, Cytoplasmic and Nuclear
Ubiquitins
UBR5 protein, human
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

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