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

Anthea Di Rita, Angelo Peschiaroli, Pasquale D′Acunzo, Daniela Strobbe, Zehan Hu, Jens Gruber, Mads Nygaard, Matteo Lambrughi, Gerry Melino, Elena Papaleo, Jörn Dengjel, Said El Alaoui, Michelangelo Campanella, Volker Dötsch, Vladimir V. Rogov, Flavie Strappazzon () and Francesco Cecconi ()
Additional contact information
Anthea Di Rita: University of Rome Tor Vergata
Angelo Peschiaroli: Institute of Translational Pharmacology IFT
Pasquale D′Acunzo: IRCCS Bambino Gesù Children’s Hospital
Daniela Strobbe: University of Rome Tor Vergata
Zehan Hu: University of Fribourg
Jens Gruber: Goethe University
Mads Nygaard: Danish Cancer Society Research Center
Matteo Lambrughi: Danish Cancer Society Research Center
Gerry Melino: University of Rome Tor Vergata
Elena Papaleo: Danish Cancer Society Research Center
Jörn Dengjel: University of Fribourg
Said El Alaoui: Covalab
Michelangelo Campanella: IRCCS- Regina Elena, National Cancer Institute
Volker Dötsch: Goethe University
Vladimir V. Rogov: Goethe University
Flavie Strappazzon: University of Rome Tor Vergata
Francesco Cecconi: University of Rome Tor Vergata

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05722-3

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