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

A. Di Rita, A. Peschiaroli, P. D Acunzo, D. Strobbe, Z. Hu, J. Gruber, M. Nygaard, M. Lambrughi, G. Melino, E. Papaleo, J. Dengjel, S. El Alaoui, M. Campanella, V. Dotsch, V. V. Rogov, F. Strappazzon, F. Cecconi

Research output: Contribution to journalArticlepeer-review

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 IKKalpha 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 IKKalpha are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.
Original languageEnglish
Pages (from-to)3755
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Sep 14 2018

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