HUWE1 E3 ligase promotes PINK1/PARKINindependent mitophagy by regulating AMBRA1 activation via IKKa

Di Rita, A; Peschiaroli, A; D'Acunzo, P; Strobbe, D; Hu, Z; Gruber, J; Mygaard, M; Lambrughi, M; Melino, G; Papaleo, E; Dengiel, J; El Alaoui, S; Campanella, M; Dötsch, V; Rogov, V V; Strappazzon, F; Cecconi, F

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.

Citation

Di Rita, A., Peschiaroli, A., D'Acunzo, P., Strobbe, D., Hu, Z., Gruber, J., …Cecconi, F. (2018). HUWE1 E3 ligase promotes PINK1/PARKINindependent mitophagy by regulating AMBRA1 activation via IKKa. Nature Communications, 9(3755), https://doi.org/10.1038/s41467-018-05722-3

• Journal Article Type: Article
• Acceptance Date: Jun 27, 2018
• Publication Date: Sep 14, 2018
• Deposit Date: Oct 5, 2018
• Publicly Available Date: Oct 15, 2018
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 3755
• DOI: https://doi.org/10.1038/s41467-018-05722-3
• Public URL: https://rvc-repository.worktribe.com/output/1385886