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

Mads Daugaard, Roberto Nitsch, Babak Razaghi, Lindsay McDonald, Ameer Jarrar, Stéphanie Torrino, Sonia Castillo-Lluva, Barak Rotblat, Liheng Li, Angeliki Malliri, Emmanuel Lemichez, Amel Mettouchi, Jason N. Berman, Josef M. Penninger and Poul H. Sorensen ()
Additional contact information
Mads Daugaard: British Columbia Cancer Research Centre
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

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3180

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