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The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling

Author

Listed:
  • Sara Kassel

    (Vanderbilt University)

  • Kai Yuan

    (Dartmouth College)

  • Nawat Bunnag

    (Dartmouth College
    Dartmouth College)

  • Leif R. Neitzel

    (Michigan State University College of Human Medicine)

  • Wenhui Lu

    (Georgetown University)

  • Anna Schwarzkopf

    (Vanderbilt University)

  • Benjamin Maines

    (Dartmouth College)

  • Matthew A. Loberg

    (Vanderbilt University Medical Center)

  • George Xu

    (Vanderbilt University Medical Center)

  • Amber Adams

    (Dartmouth College)

  • Andrew D. McCray

    (Dartmouth College)

  • Alex Cho

    (Vanderbilt University)

  • Mary Rockouski

    (Vanderbilt University)

  • Gemma Orton

    (Vanderbilt University)

  • Lily Goldsmith

    (Vanderbilt University)

  • Md Mubtaseem Ahnaf Aronno

    (Dartmouth College)

  • Zachary T. Spencer

    (Dartmouth College)

  • Omar M. Khan

    (Hamad Bin Khalifa University)

  • Fei Ye

    (Vanderbilt University Medical Center)

  • Charles Williams

    (Michigan State University College of Human Medicine)

  • Andres M. Lebensohn

    (National Institutes of Health)

  • Rajat Rohatgi

    (Stanford University School of Medicine)

  • Xiaofeng Wang

    (Dartmouth College
    Dartmouth College)

  • Vivian L. Weiss

    (Vanderbilt University Medical Center)

  • Charles C. Hong

    (Michigan State University College of Human Medicine)

  • Arminja N. Kettenbach

    (Dartmouth College
    Dartmouth College)

  • David J. Robbins

    (Georgetown University)

  • Yashi Ahmed

    (Dartmouth College
    Dartmouth College)

  • Ethan Lee

    (Vanderbilt University
    Vanderbilt University School of Medicine)

Abstract

SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes displace nucleosomes to promote the access of transcription factors to enhancers and promoters. Despite the critical roles of SWI/SNF in animal development and tumorigenesis, how signaling pathways recruit SWI/SNF complexes to their target genes is unclear. Here, we demonstrate that target gene activation mediated by β-catenin, the essential transcriptional coactivator in the Wnt signal transduction pathway, requires ubiquitylation of the SWI/SNF component Brahma-related gene-1 (BRG1) by the E3 ubiquitin ligase Thyroid Hormone Receptor Interactor 12 (TRIP12). TRIP12 depletion in Drosophila, zebrafish, mouse organoids, and human cells attenuates Wnt signaling. Genetic epistasis experiments place TRIP12 activity downstream of the β-catenin destruction complex. TRIP12 interacts with and ubiquitylates BRG1, and BRG1 depletion blocks TRIP12-mediated Wnt pathway activation. TRIP12 promotes BRG1 binding to β-catenin in the presence of Wnt. Our findings support a model in which TRIP12 ubiquitylates BRG1 in the presence of Wnt and promotes its interaction with β-catenin in the nucleus, in order to recruit SWI/SNF to Wnt target genes. Our studies suggest a general mechanism by which cell signaling induces the interaction between BRG1 and pathway-specific transcription factors to recruit SWI/SNF complexes to their appropriate target genes.

Suggested Citation

  • Sara Kassel & Kai Yuan & Nawat Bunnag & Leif R. Neitzel & Wenhui Lu & Anna Schwarzkopf & Benjamin Maines & Matthew A. Loberg & George Xu & Amber Adams & Andrew D. McCray & Alex Cho & Mary Rockouski & , 2025. "The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60535-5
    DOI: 10.1038/s41467-025-60535-5
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    References listed on IDEAS

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    1. Sandi Radko-Juettner & Hong Yue & Jacquelyn A. Myers & Raymond D. Carter & Alexis N. Robertson & Priya Mittal & Zhexin Zhu & Baranda S. Hansen & Katherine A. Donovan & Moritz Hunkeler & Wojciech Rosik, 2024. "Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF," Nature, Nature, vol. 628(8007), pages 442-449, April.
    2. Robert A. Cavallo & Rachel T. Cox & Melissa M. Moline & Jeroen Roose & Gordon A. Polevoy & Hans Clevers & Mark Peifer & Amy Bejsovec, 1998. "Drosophila Tcf and Groucho interact to repress Wingless signalling activity," Nature, Nature, vol. 395(6702), pages 604-608, October.
    3. Hikaru Tsuchiya & Daocharad Burana & Fumiaki Ohtake & Naoko Arai & Ai Kaiho & Masayuki Komada & Keiji Tanaka & Yasushi Saeki, 2018. "Ub-ProT reveals global length and composition of protein ubiquitylation in cells," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    4. Sandi Radko-Juettner & Hong Yue & Jacquelyn A. Myers & Raymond D. Carter & Alexis N. Robertson & Priya Mittal & Zhexin Zhu & Baranda S. Hansen & Katherine A. Donovan & Moritz Hunkeler & Wojciech Rosik, 2024. "Author Correction: Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF," Nature, Nature, vol. 629(8012), pages 12-12, May.
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