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Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1

Author

Listed:
  • Salima Daou

    (University of Montréal
    Sinai Health System)

  • Haithem Barbour

    (University of Montréal)

  • Oumaima Ahmed

    (University of Montréal)

  • Louis Masclef

    (University of Montréal)

  • Caroline Baril

    (University of Montréal)

  • Nadine Nkwe

    (University of Montréal)

  • Daméhan Tchelougou

    (University of Montréal)

  • Maxime Uriarte

    (University of Montréal)

  • Eric Bonneil

    (University of Montréal)

  • Derek Ceccarelli

    (Sinai Health System)

  • Nazar Mashtalir

    (University of Montréal)

  • Mika Tanji

    (University of Hawaii Cancer Center, University of Hawaii)

  • Jean-Yves Masson

    (Laval University Cancer Research Center, 9 McMahon)

  • Pierre Thibault

    (University of Montréal)

  • Frank Sicheri

    (Sinai Health System)

  • Haining Yang

    (University of Hawaii Cancer Center, University of Hawaii)

  • Michele Carbone

    (University of Hawaii Cancer Center, University of Hawaii)

  • Marc Therrien

    (University of Montréal
    University of Montréal)

  • El Bachir Affar

    (University of Montréal)

Abstract

The tumor suppressor and deubiquitinase (DUB) BAP1 and its Drosophila ortholog Calypso assemble DUB complexes with the transcription regulators Additional sex combs-like (ASXL1, ASXL2, ASXL3) and Asx respectively. ASXLs and Asx use their DEUBiquitinase ADaptor (DEUBAD) domain to stimulate BAP1/Calypso DUB activity. Here we report that monoubiquitination of the DEUBAD is a general feature of ASXLs and Asx. BAP1 promotes DEUBAD monoubiquitination resulting in an increased stability of ASXL2, which in turn stimulates BAP1 DUB activity. ASXL2 monoubiquitination is directly catalyzed by UBE2E family of Ubiquitin-conjugating enzymes and regulates mammalian cell proliferation. Remarkably, Calypso also regulates Asx monoubiquitination and transgenic flies expressing monoubiquitination-defective Asx mutant exhibit developmental defects. Finally, the protein levels of ASXL2, BAP1 and UBE2E enzymes are highly correlated in mesothelioma tumors suggesting the importance of this signaling axis for tumor suppression. We propose that monoubiquitination orchestrates a molecular symbiosis relationship between ASXLs and BAP1.

Suggested Citation

  • Salima Daou & Haithem Barbour & Oumaima Ahmed & Louis Masclef & Caroline Baril & Nadine Nkwe & Daméhan Tchelougou & Maxime Uriarte & Eric Bonneil & Derek Ceccarelli & Nazar Mashtalir & Mika Tanji & Je, 2018. "Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1," Nature Communications, Nature, vol. 9(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06854-2
    DOI: 10.1038/s41467-018-06854-2
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    Cited by:

    1. Nidhi Rohatgi & Wei Zou & Yongjia Li & Kevin Cho & Patrick L. Collins & Eric Tycksen & Gaurav Pandey & Carl J. DeSelm & Gary J. Patti & Anwesha Dey & Steven L. Teitelbaum, 2023. "BAP1 promotes osteoclast function by metabolic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Yi Zhang & Guojia Xie & Ji-Eun Lee & Mohamad Zandian & Deepthi Sudarshan & Benjamin Estavoyer & Caroline Benz & Tiina Viita & Golareh Asgaritarghi & Catherine Lachance & Clémence Messmer & Leandro Sim, 2024. "ASXLs binding to the PHD2/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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