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

Author

Listed:
  • Anthea Di Rita

    (University of Rome Tor Vergata
    IRCCS Bambino Gesù Children’s Hospital
    IRCCS FONDAZIONE SANTA LUCIA)

  • Angelo Peschiaroli

    (Institute of Translational Pharmacology IFT)

  • Pasquale D′Acunzo

    (IRCCS Bambino Gesù Children’s Hospital)

  • Daniela Strobbe

    (University of Rome Tor Vergata
    IRCCS- Regina Elena, National Cancer Institute)

  • Zehan Hu

    (University of Fribourg)

  • Jens Gruber

    (Goethe University)

  • Mads Nygaard

    (Danish Cancer Society Research Center)

  • Matteo Lambrughi

    (Danish Cancer Society Research Center)

  • Gerry Melino

    (University of Rome Tor Vergata)

  • Elena Papaleo

    (Danish Cancer Society Research Center)

  • Jörn Dengjel

    (University of Fribourg)

  • Said El Alaoui

    (Covalab)

  • Michelangelo Campanella

    (IRCCS- Regina Elena, National Cancer Institute
    Royal Veterinary College
    University College London)

  • Volker Dötsch

    (Goethe University)

  • Vladimir V. Rogov

    (Goethe University)

  • Flavie Strappazzon

    (University of Rome Tor Vergata
    IRCCS FONDAZIONE SANTA LUCIA)

  • Francesco Cecconi

    (University of Rome Tor Vergata
    IRCCS Bambino Gesù Children’s Hospital
    Danish Cancer Society Research Center)

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.

Suggested Citation

  • 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 & Mi, 2018. "HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05722-3
    DOI: 10.1038/s41467-018-05722-3
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    Cited by:

    1. Ara Lee & Gihyun Sung & Sanghee Shin & Song-Yi Lee & Jaehwan Sim & Truong Thi My Nhung & Tran Diem Nghi & Sang Ki Park & Ponnusamy Pon Sathieshkumar & Imkyeung Kang & Ji Young Mun & Jong-Seo Kim & Hyu, 2024. "OrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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