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

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 
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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Metadaten
Author:Anthea Di Rita, Angelo Peschiaroli, Pasquale D′Acunzo, Daniela Strobbe, Zehan Hu, Jens Gruber, Mads Nygaard, Matteo Lambrughi, Gerry Melino, Elena Papaleo, Jörn Dengjel, Saïd El Alaoui, Michelangelo Campanella, Volker Dötsch, Vladimir V. Rogov, Flavie Strappazzon, Francesco Cecconi
URN:urn:nbn:de:hebis:30:3-488641
DOI:http://dx.doi.org/10.1038/s41467-018-05722-3
ISSN:2041-1723
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=30217973
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/09/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/02/07
Tag:Mitophagy; Phosphorylation
Volume:9
Issue:1, Art. 3755
Pagenumber:18
First Page:1
Last Page:18
Note:
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
HeBIS PPN:446229989
Institutes:Biochemie und Chemie
Exzellenzcluster Makromolekulare Komplexe
Zentrum für Biomolekulare Magnetische Resonanz (BMRZ)
Dewey Decimal Classification:570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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