1. Academic Validation
  2. HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

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

  • Nat Commun. 2018 Sep 14;9(1):3755. doi: 10.1038/s41467-018-05722-3.
Anthea Di Rita 1 2 3 Angelo Peschiaroli 4 Pasquale D Acunzo 2 Daniela Strobbe 1 5 Zehan Hu 6 Jens Gruber 7 Mads Nygaard 8 Matteo Lambrughi 8 Gerry Melino 9 Elena Papaleo 8 Jörn Dengjel 6 Said El Alaoui 10 Michelangelo Campanella 5 11 12 Volker Dötsch 7 Vladimir V Rogov 7 Flavie Strappazzon 13 14 Francesco Cecconi 15 16 17
Affiliations

Affiliations

  • 1 Department of Biology, University of Rome Tor Vergata, 00133, Rome, Italy.
  • 2 Department of Paediatric Haematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • 3 IRCCS FONDAZIONE SANTA LUCIA, 00143, Rome, Italy.
  • 4 National Research Council of Italy (CNR), Institute of Translational Pharmacology IFT, Via Fosso del Cavaliere 100, 00133, Rome, Italy.
  • 5 IRCCS- Regina Elena, National Cancer Institute, 00133, Rome, Italy.
  • 6 Department of Biology, University of Fribourg, Fribourg, Switzerland.
  • 7 Institute of Biophysical and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.
  • 8 Computational Biology Laboratory, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
  • 9 Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133, Rome, Italy.
  • 10 Covalab, Villeurbanne, France.
  • 11 Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, UK.
  • 12 University College London Consortium for Mitochondrial Research, University College London, London, WC1 6BT, UK.
  • 13 Department of Biology, University of Rome Tor Vergata, 00133, Rome, Italy. f.strappazzon@hsantalucia.it.
  • 14 IRCCS FONDAZIONE SANTA LUCIA, 00143, Rome, Italy. f.strappazzon@hsantalucia.it.
  • 15 Department of Biology, University of Rome Tor Vergata, 00133, Rome, Italy. cecconi@cancer.dk.
  • 16 Department of Paediatric Haematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. cecconi@cancer.dk.
  • 17 Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark. cecconi@cancer.dk.
Abstract

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.

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