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
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
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- RERO DOC 323278
- DOI 10.1038/s41467-018-05722-3
- Persistent URL
- https://folia.unifr.ch/unifr/documents/307004
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