PMID:30217973

Citation	Di Rita, A, Peschiaroli, A, D Acunzo, P, Strobbe, D, Hu, Z, Gruber, J, Nygaard, M, Lambrughi, M, Melino, G, Papaleo, E, Dengjel, J, El Alaoui, S, Campanella, M, Dötsch, V, Rogov, VV, Strappazzon, F and Cecconi, F (2018) HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. Nat Commun 9:3755
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.
Links	PubMed Online version:10.1038/s41467-018-05722-3
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MACFA:FOXP3	enables	GO:0004674: protein serine/threonine kinase activity	ECO:0000314: direct assay evidence used in manual assertion		F	has_input:(UniProtKB:Q9C0C7) positively_regulates:(GO:0000423)	Seeded From UniProt	complete
HUMAN:HUWE1	enables	GO:0061630: ubiquitin protein ligase activity	ECO:0000314: direct assay evidence used in manual assertion		F	has_input:(UniProtKB:O95140) part_of:(GO:0000209) positively_regulates:(GO:0000423)	Seeded From UniProt	complete
HUMAN:HUWE1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9C0C7	F		Seeded From UniProt	complete
HUMAN:AMRA1	involved_in	GO:1901526: positive regulation of mitophagy	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:AMRA1	involved_in	GO:0000209: protein polyubiquitination	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:AMRA1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q7Z6Z7	F		Seeded From UniProt	complete
HUMAN:HUWE1		GO:0098779: positive regulation of mitophagy in response to mitochondrial depolarization	ECO:0000314:		P		Figure 1 and Supplementary Fig. 1- It is positive regulation of mitophagy because HUWE1 depletion impairs AMBRA1-mediated mitophagy. The O/A treatments are indicative of mitochondrial depolarization. Supplementary Table 1- The Bethyl catalogue number for the HUWE1 antibody tells us that the protein is a human protein. Organism- Human	complete CACAO 13323

References

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