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USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

Author

Listed:
  • Lei Ji

    (Novartis Pharma AG)

  • Bo Lu

    (Novartis Pharma AG)

  • Raffaella Zamponi

    (Novartis Pharma AG
    Azienda USL—IRCCS di Reggio Emilia)

  • Olga Charlat

    (Novartis Pharma AG)

  • Robert Aversa

    (Novartis Pharma AG)

  • Zinger Yang

    (Novartis Pharma AG)

  • Frederic Sigoillot

    (Novartis Pharma AG)

  • Xiaoping Zhu

    (Novartis Pharma AG)

  • Tiancen Hu

    (Novartis Pharma AG)

  • John S. Reece-Hoyes

    (Novartis Pharma AG)

  • Carsten Russ

    (Novartis Pharma AG)

  • Gregory Michaud

    (Novartis Pharma AG)

  • Jan S. Tchorz

    (Novartis Pharma AG)

  • Xiaomo Jiang

    (Novartis Pharma AG)

  • Feng Cong

    (Novartis Pharma AG)

Abstract

Axin is a key scaffolding protein responsible for the formation of the β-catenin destruction complex. Stability of Axin protein is regulated by the ubiquitin-proteasome system, and modulation of cellular concentration of Axin protein has a profound effect on Wnt/β-catenin signaling. Although E3s promoting Axin ubiquitination have been identified, the deubiquitinase responsible for Axin deubiquitination and stabilization remains unknown. Here, we identify USP7 as a potent negative regulator of Wnt/β-catenin signaling through CRISPR screens. Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt/β-catenin signaling in multiple cellular systems. USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin. Inhibition of USP7 regulates osteoblast differentiation and adipocyte differentiation through increasing Wnt/β-catenin signaling. Our study reveals a critical mechanism that prevents excessive degradation of Axin and identifies USP7 as a target for sensitizing cells to Wnt/β-catenin signaling.

Suggested Citation

  • Lei Ji & Bo Lu & Raffaella Zamponi & Olga Charlat & Robert Aversa & Zinger Yang & Frederic Sigoillot & Xiaoping Zhu & Tiancen Hu & John S. Reece-Hoyes & Carsten Russ & Gregory Michaud & Jan S. Tchorz , 2019. "USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12143-3
    DOI: 10.1038/s41467-019-12143-3
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    Cited by:

    1. George Andrei Crauciuc & Mihaela Iancu & Peter Olah & Florin Tripon & Mădălina Anciuc & Liliana Gozar & Rodica Togănel & Claudia Bănescu, 2020. "Significant Associations between AXIN1 rs1805105, rs12921862, rs370681 Haplotypes and Variant Genotypes of AXIN2 rs2240308 with Risk of Congenital Heart Defects," IJERPH, MDPI, vol. 17(20), pages 1-12, October.
    2. Juan Li & Yang Wang & Yue Luo & Yang Liu & Yong Yi & Jinsong Li & Yang Pan & Weiyuxin Li & Wanbang You & Qingyong Hu & Zhiqiang Zhao & Yujun Zhang & Yang Cao & Lingqiang Zhang & Junying Yuan & Zhi-Xio, 2022. "USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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