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

Rita, Anthea Di; Peschiaroli, Angelo; D?Acunzo, Pasquale; Strobbe, Daniela; Hu, Zehan; Gruber, Jens; Nygaard, Mads; Lambrughi, Matteo; Melino, Gerry; Papaleo, Elena; Dengjel, Jörn; Alaoui, Said El; Campanella, Michelangelo; Dötsch, Volker; Rogov, Vladimir V.; Strappazzon, Flavie; Cecconi, Francesco

doi:10.1038/s41467-018-05722-3

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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

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