HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha

A. Di Rita, A. Peschiaroli, P. D Acunzo, D. Strobbe, Z. Hu, J. Gruber, M. Nygaard, M. Lambrughi, G. Melino, E. Papaleo, J. Dengjel, S. El Alaoui, M. Campanella, V. Dotsch, V. V. Rogov, F. Strappazzon, F. Cecconi

Research output: Contribution to journalArticle

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 IKKalpha 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 IKKalpha are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.
Original languageEnglish
Pages (from-to)3755
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Sep 14 2018

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Mitochondrial Degradation
homeostasis
Phosphorylation
Mitochondria
Ubiquitin-Protein Ligases
regulators
Serine
Quality control
Tumors
Phosphotransferases
Aging of materials
Chemical activation
Cells
activation
phosphorylation
Molecules
mitochondria
quality control
luminaires
Proteins

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Rita, A. D., Peschiaroli, A., Acunzo, P. D., Strobbe, D., Hu, Z., Gruber, J., ... Cecconi, F. (2018). HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha. Nature Communications, 9(1), 3755. https://doi.org/10.1038/s41467-018-05722-3 [doi]

HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha. / Rita, A. Di; Peschiaroli, A.; Acunzo, P. D; Strobbe, D.; Hu, Z.; Gruber, J.; Nygaard, M.; Lambrughi, M.; Melino, G.; Papaleo, E.; Dengjel, J.; Alaoui, S. El; Campanella, M.; Dotsch, V.; Rogov, V. V.; Strappazzon, F.; Cecconi, F.

In: Nature Communications, Vol. 9, No. 1, 14.09.2018, p. 3755.

Research output: Contribution to journalArticle

Rita, AD, Peschiaroli, A, Acunzo, PD, Strobbe, D, Hu, Z, Gruber, J, Nygaard, M, Lambrughi, M, Melino, G, Papaleo, E, Dengjel, J, Alaoui, SE, Campanella, M, Dotsch, V, Rogov, VV, Strappazzon, F & Cecconi, F 2018, 'HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha', Nature Communications, vol. 9, no. 1, pp. 3755. https://doi.org/10.1038/s41467-018-05722-3 [doi]
Rita, A. Di ; Peschiaroli, A. ; Acunzo, P. D ; Strobbe, D. ; Hu, Z. ; Gruber, J. ; Nygaard, M. ; Lambrughi, M. ; Melino, G. ; Papaleo, E. ; Dengjel, J. ; Alaoui, S. El ; Campanella, M. ; Dotsch, V. ; Rogov, V. V. ; Strappazzon, F. ; Cecconi, F. / HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha. In: Nature Communications. 2018 ; Vol. 9, No. 1. pp. 3755.
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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 IKKalpha 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 IKKalpha are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.",
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AU - Rita, A. Di

AU - Peschiaroli, A.

AU - Acunzo, P. D

AU - Strobbe, D.

AU - Hu, Z.

AU - Gruber, J.

AU - Nygaard, M.

AU - Lambrughi, M.

AU - Melino, G.

AU - Papaleo, E.

AU - Dengjel, J.

AU - Alaoui, S. El

AU - Campanella, M.

AU - Dotsch, V.

AU - Rogov, V. V.

AU - Strappazzon, F.

AU - Cecconi, F.

N1 - LR: 20180918; JID: 101528555; 2017/10/06 00:00 [received]; 2018/06/27 00:00 [accepted]; 2018/09/16 06:00 [entrez]; 2018/09/16 06:00 [pubmed]; 2018/09/16 06:00 [medline]; epublish

PY - 2018/9/14

Y1 - 2018/9/14

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 IKKalpha 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 IKKalpha are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.

AB - 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 IKKalpha 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 IKKalpha are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.

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