期刊
CELL DEATH AND DIFFERENTIATION
卷 27, 期 4, 页码 1155-1168出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41418-019-0404-8
关键词
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资金
- Italian Ministry of Health [GR2011-02351433]
- ROCHE (Roche per la ricerca 2017)
- 5XMILLE Italian Ministry of Health (2017)
- AIRC [15523, 20473]
- MRC, LazioInnova [85-2017-14986)]
- Italian Ministry of Education, University and Research [2017WC8499]
- AIRC (Associazione Italiana Ricerca sul Cancro) [9962, 21724]
- FUV Grant 2019
- Bjarne Saxhof Foundation
- Danish Cancer Society [KBVU R72-A4408, R146-A9364]
- Novo Nordisk Foundation [7559, 22544]
- Lundbeckfonden [R2332016-3360]
- LEO Foundation [LF17024]
- Associazione Italiana per la Ricerca sul Cancro [AIRC IG-15180]
- Danmarks Grundforskningsfond [DNRF125]
- MRC [MC_U132670600, MC_UU_00025/2] Funding Source: UKRI
Receptor-mediated mitophagy is a crucial process involved in mitochondria quality control. AMBRA1 is a mitophagy receptor for the selective removal of damaged mitochondria in mammalian cells. A critical unresolved issue is how AMBRA1-mediated mitophagy is controlled in response to cellular stress. Here, we investigated the role of BCL2-family proteins on AMBRA1-dependent mitophagy and showed that MCL1 delays AMBRA1-dependent mitophagy. Indeed, MCL1 overexpression is sufficient to inhibit recruitment to mitochondria of the E3 Ubiquitin ligase HUWE1, a crucial dynamic partner of AMBRA1, upon AMBRA1-mediated mitophagy induction. In addition, we found that during mitophagy induced by AMBRA1, MCL1 levels decreased but were sustained by inhibition of the GSK-3 beta kinase, which delayed AMBRA1-mediated mitophagy. Also, we showed that MCL1 was phosphorylated by GSK-3 beta at a conserved GSK-3 phosphorylation site (S159) during AMBRA1-mediated mitophagy and that this event was accompanied by HUWE1-dependent MCL1 degradation. Altogether, our results demonstrate that MCL1 stability is regulated by the kinase GSK-3 beta and the E3 ubiquitin ligase HUWE1 in regulating AMBRA1-mediated mitophagy. Our work thus defines MCL1 as an upstream stress-sensitive protein, functional in AMBRA1-mediated mitophagy.
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