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Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes

Author

Listed:
  • Mads Daugaard

    (British Columbia Cancer Research Centre
    University of British Columbia)

  • Roberto Nitsch

    (IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences)

  • Babak Razaghi

    (Dalhousie University and IWK Health Centre)

  • Lindsay McDonald

    (Dalhousie University and IWK Health Centre)

  • Ameer Jarrar

    (Dalhousie University and IWK Health Centre)

  • Stéphanie Torrino

    (Equipe labellisée Ligue Contre Le Cancer, U1065, Centre Méditerranéen de Médecine Moléculaire, C3M, Université de Nice-Sophia-Antipolis)

  • Sonia Castillo-Lluva

    (Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester)

  • Barak Rotblat

    (British Columbia Cancer Research Centre)

  • Liheng Li

    (British Columbia Cancer Research Centre)

  • Angeliki Malliri

    (Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester)

  • Emmanuel Lemichez

    (Equipe labellisée Ligue Contre Le Cancer, U1065, Centre Méditerranéen de Médecine Moléculaire, C3M, Université de Nice-Sophia-Antipolis)

  • Amel Mettouchi

    (Equipe labellisée Ligue Contre Le Cancer, U1065, Centre Méditerranéen de Médecine Moléculaire, C3M, Université de Nice-Sophia-Antipolis)

  • Jason N. Berman

    (Dalhousie University and IWK Health Centre)

  • Josef M. Penninger

    (IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences)

  • Poul H. Sorensen

    (British Columbia Cancer Research Centre
    University of British Columbia)

Abstract

The Hace1-HECT E3 ligase is a tumor suppressor that ubiquitylates the activated GTP-bound form of the Rho family GTPase Rac1, leading to Rac1 proteasomal degradation. Here we show that, in vertebrates, Hace1 targets Rac1 for degradation when Rac1 is localized to the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase holoenzyme. This event blocks de novo reactive oxygen species generation by Rac1-dependent NADPH oxidases, and thereby confers cellular protection from reactive oxygen species-induced DNA damage and cyclin D1-driven hyper-proliferation. Genetic inactivation of Hace1 in mice or zebrafish, as well as Hace1 loss in human tumor cell lines or primary murine or human tumors, leads to chronic NADPH oxidase-dependent reactive oxygen species elevation, DNA damage responses and enhanced cyclin D1 expression. Our data reveal a conserved ubiquitin-dependent molecular mechanism that controls the activity of Rac1-dependent NADPH oxidase complexes, and thus constitutes the first known example of a tumor suppressor protein that directly regulates reactive oxygen species production in vertebrates.

Suggested Citation

  • Mads Daugaard & Roberto Nitsch & Babak Razaghi & Lindsay McDonald & Ameer Jarrar & Stéphanie Torrino & Sonia Castillo-Lluva & Barak Rotblat & Liheng Li & Angeliki Malliri & Emmanuel Lemichez & Amel Me, 2013. "Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes," Nature Communications, Nature, vol. 4(1), pages 1-13, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3180
    DOI: 10.1038/ncomms3180
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    Cited by:

    1. Serena Petracchini & Daniel Hamaoui & Anne Doye & Atef Asnacios & Florian Fage & Elisa Vitiello & Martial Balland & Sebastien Janel & Frank Lafont & Mukund Gupta & Benoit Ladoux & Jerôme Gilleron & Te, 2022. "Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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