HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα
Year: 2018
Type: article
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.
Source: Nature Communications
Institutions: University of Rome Tor Vergata, Bambino Gesù Children's Hospital, Fondazione Santa Lucia, Istituti di Ricovero e Cura a Carattere Scientifico, Istituto di Farmacologia Traslazionale, National Research Council, Instituto Nazionale Tumori Regina Elena, University of Fribourg, Goethe University Frankfurt, Danish Cancer Society, Covalab (France), Royal Veterinary College, University College London
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Kræftens Bekæmpelse, European Commission, National Research Foundation, Deutsche Forschungsgemeinschaft, Danmarks Grundforskningsfond, Partnership for Advanced Computing in Europe AISBL, Ministero della Salute, Lundbeckfonden, Novo Nordisk, Associazione Italiana per la Ricerca sul Cancro, Novo Nordisk Fonden, LEO Fondet, Medical Research Council, Biotechnology and Biological Sciences Research Council
Awards: G114120683, G1252650050, G2192319387, G3333118130, G3758706485, G3761877457, G382026437, Exploiting MELanoma disease comPLEXity to address European research training needs in translational cancer systems biology and cancer systems medicine, G434337789, The Resilient Brain. Imaging Biomarkers of Brain Metabolic Reserve, G5290293035, G602105495, G6309488628, The role of p53/p73 family members in the cytotoxic response, G7110020941, G8206886958, G898267003
OpenAlex ID: W2890021586