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

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.

PMID: 30217973 DOI: 10.1038/s41467-018-05722-3

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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