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HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

  • Rita, Anthea Di Department of Biology, University of Rome Tor Vergata, Italy - Department of Paediatric Haematology Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children?s Hospital, Rome, Italy - IRCCS FONDAZIONE SANTA LUCIA, Rome, Italy
  • Peschiaroli, Angelo National Research Council of Italy (CNR), Institute of Translational Pharmacology IFT, Rome, Italy
  • D?Acunzo, Pasquale Department of Paediatric Haematology Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children?s Hospital, Rome, Italy
  • Strobbe, Daniela Department of Biology, University of Rome Tor Vergata, Italy - IRCCS- Regina Elena, National Cancer Institute, Rome, Italy
  • Hu, Zehan Department of Biology, University of Fribourg, Switzerland
  • Gruber, Jens Institute of Biophysical and Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Germany
  • Nygaard, Mads Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark
  • Lambrughi, Matteo Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark
  • Melino, Gerry Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy
  • Papaleo, Elena Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark
  • Dengjel, Jörn Department of Biology, University of Fribourg, Switzerland
  • Alaoui, Said El Covalab, Villeurbanne, France
  • Campanella, Michelangelo IRCCS- Regina Elena, National Cancer Institute, Rome, Italy - Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK - University College London Consortium for Mitochondrial Research, University College London, London, UK
  • Dötsch, Volker Institute of Biophysical and Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Germany
  • Rogov, Vladimir V. Institute of Biophysical and Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Germany
  • Strappazzon, Flavie Department of Biology, University of Rome Tor Vergata, Italy - IRCCS FONDAZIONE SANTA LUCIA, Rome, Italy
  • Cecconi, Francesco Department of Biology, University of Rome Tor Vergata, Italy - Department of Paediatric Haematology Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children?s Hospital, Rome, Italy - Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark
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    14.09.2018
Published in:
  • Nature Communications. - 2018, vol. 9, no. 1, p. 3755
English The selective removal of undesired or damaged mitochondria by autophagy, known as mitophagy, is crucial for cellular homoeostasis, and prevents tumour diffusion, neurodegeneration and ageing. The pro-autophagic molecule AMBRA1 (autophagy/beclin-1 regulator-1) has been defined as a novel regulator of mitophagy in both PINK1/PARKIN-dependent and -independent systems. Here, we identified the E3 ubiquitin ligase HUWE1 as a key inducing factor in AMBRA1-mediated mitophagy, a process that takes place independently of the main mitophagy receptors. Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014. This modification is mediated by the IKKα kinase and induces structural changes in AMBRA1, thus promoting its interaction with LC3/GABARAP (mATG8) proteins and its mitophagic activity. Altogether, these results demonstrate that AMBRA1 regulates mitophagy through a novel pathway, in which HUWE1 and IKKα are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.
Faculty
Faculté des sciences et de médecine
Department
Département de Biologie
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/307004
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