TY  - JOUR
A1  - Di Rita, Anthea
A1  - Peschiaroli, Angelo
A1  - D′Acunzo, Pasquale
A1  - Strobbe, Daniela
A1  - Hu, Zehan
A1  - Gruber, Jens
A1  - Nygaard, Mads
A1  - Lambrughi, Matteo
A1  - Melino, Gerry
A1  - Papaleo, Elena
A1  - Dengjel, Jörn
A1  - Alaoui, Saïd El
A1  - Campanella, Michelangelo
A1  - Dötsch, Volker
A1  - Rogov, Vladimir V.
A1  - Strappazzon, Flavie
A1  - Cecconi, Francesco
T1  - HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα
T2  - Nature Communications
N2  - 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.
KW  - Mitophagy
KW  - Phosphorylation
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48864
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-488641
SN  - 2041-1723
N1  - 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/.
VL  - 9
IS  - 1, Art. 3755
SP  - 1
EP  - 18
PB  - Nature Publishing Group UK
CY  - [London]
ER  -