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

Anthea Di Rita; Angelo Peschiaroli; Pasquale D Acunzo; Daniela Strobbe; Zehan Hu; Jens Gruber; Mads Nygaard; Matteo Lambrughi; Gerry Melino; Elena Papaleo; Jörn Dengjel; Said El Alaoui; Michelangelo Campanella; Volker Dötsch; Vladimir V Rogov; Flavie Strappazzon; Francesco Cecconi

doi:10.1038/s41467-018-05722-3

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

Anthea Di Rita, Angelo Peschiaroli, Pasquale D Acunzo, Daniela Strobbe, Zehan Hu, Jens Gruber, Mads Nygaard, Matteo Lambrughi, Gerry Melino, Elena Papaleo, Jörn Dengjel, Said El Alaoui, Michelangelo Campanella, Volker Dötsch, Vladimir V Rogov, Flavie Strappazzon, Francesco Cecconi

Research output: Contribution to journal › 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.

Original language	English
Number of pages	18
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05722-3
Publication status	Published - Sep 14 2018

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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, V. V., Strappazzon, F., & Cecconi, F. (2018). HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-05722-3

HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. / Di Rita, Anthea; Peschiaroli, Angelo; D Acunzo, Pasquale; Strobbe, Daniela; Hu, Zehan; Gruber, Jens; Nygaard, Mads; Lambrughi, Matteo; Melino, Gerry; Papaleo, Elena; Dengjel, Jörn; El Alaoui, Said; Campanella, Michelangelo; Dötsch, Volker; Rogov, Vladimir V; Strappazzon, Flavie ; Cecconi, Francesco.

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

Research output: Contribution to journal › Article

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 & Cecconi, F 2018, 'HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα', Nature Communications, vol. 9, no. 1. https://doi.org/10.1038/s41467-018-05722-3

Di Rita, Anthea ; Peschiaroli, Angelo ; D Acunzo, Pasquale ; Strobbe, Daniela ; Hu, Zehan ; Gruber, Jens ; Nygaard, Mads ; Lambrughi, Matteo ; Melino, Gerry ; Papaleo, Elena ; Dengjel, Jörn ; El Alaoui, Said ; Campanella, Michelangelo ; Dötsch, Volker ; Rogov, Vladimir V ; Strappazzon, Flavie ; Cecconi, Francesco. / HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. In: Nature Communications. 2018 ; Vol. 9, No. 1.

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title = "HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα",

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.",

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AU - Peschiaroli, Angelo

AU - D Acunzo, Pasquale

AU - Strobbe, Daniela

AU - Hu, Zehan

AU - Gruber, Jens

AU - Nygaard, Mads

AU - Lambrughi, Matteo

AU - Melino, Gerry

AU - Papaleo, Elena

AU - Dengjel, Jörn

AU - El Alaoui, Said

AU - Campanella, Michelangelo

AU - Dötsch, Volker

AU - Rogov, Vladimir V

AU - Strappazzon, Flavie

AU - Cecconi, Francesco

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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 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.

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 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.

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