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PMID:30217973

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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

Keywords


Significance

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

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

Notes

See also

References

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