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SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection

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  • Nils C. Gassen

    (Max Planck Institute of Psychiatry
    University of Bonn)

  • Daniela Niemeyer

    (Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
    German Centre for Infection Research (DZIF))

  • Doreen Muth

    (Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
    German Centre for Infection Research (DZIF))

  • Victor M. Corman

    (Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
    German Centre for Infection Research (DZIF))

  • Silvia Martinelli

    (Max Planck Institute of Psychiatry)

  • Alwine Gassen

    (Ludwig-Maximilian-University Munich (LMU))

  • Kathrin Hafner

    (Max Planck Institute of Psychiatry)

  • Jan Papies

    (Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
    German Centre for Infection Research (DZIF))

  • Kirstin Mösbauer

    (Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
    German Centre for Infection Research (DZIF))

  • Andreas Zellner

    (Max Planck Institute of Psychiatry)

  • Anthony S. Zannas

    (Max Planck Institute of Psychiatry
    Duke University Medical Center
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hil)

  • Alexander Herrmann

    (HIV-Cell-Interactions Group, Institute of Virology, German Research Center for Environmental Health)

  • Florian Holsboer

    (Max Planck Institute of Psychiatry)

  • Ruth Brack-Werner

    (HIV-Cell-Interactions Group, Institute of Virology, German Research Center for Environmental Health)

  • Michael Boshart

    (Ludwig-Maximilian-University Munich (LMU))

  • Bertram Müller-Myhsok

    (Max Planck Institute of Psychiatry
    Institute of Translational Medicine, University of Liverpool
    Munich Cluster for Systems Neurology - SYNERGY)

  • Christian Drosten

    (Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
    German Centre for Infection Research (DZIF))

  • Marcel A. Müller

    (Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
    German Centre for Infection Research (DZIF)
    Sechenov University)

  • Theo Rein

    (Max Planck Institute of Psychiatry
    Ludwig-Maximilian-University Munich (LMU))

Abstract

Autophagy is an essential cellular process affecting virus infections and other diseases and Beclin1 (BECN1) is one of its key regulators. Here, we identified S-phase kinase-associated protein 2 (SKP2) as E3 ligase that executes lysine-48-linked poly-ubiquitination of BECN1, thus promoting its proteasomal degradation. SKP2 activity is regulated by phosphorylation in a hetero-complex involving FKBP51, PHLPP, AKT1, and BECN1. Genetic or pharmacological inhibition of SKP2 decreases BECN1 ubiquitination, decreases BECN1 degradation and enhances autophagic flux. Middle East respiratory syndrome coronavirus (MERS-CoV) multiplication results in reduced BECN1 levels and blocks the fusion of autophagosomes and lysosomes. Inhibitors of SKP2 not only enhance autophagy but also reduce the replication of MERS-CoV up to 28,000-fold. The SKP2-BECN1 link constitutes a promising target for host-directed antiviral drugs and possibly other autophagy-sensitive conditions.

Suggested Citation

  • Nils C. Gassen & Daniela Niemeyer & Doreen Muth & Victor M. Corman & Silvia Martinelli & Alwine Gassen & Kathrin Hafner & Jan Papies & Kirstin Mösbauer & Andreas Zellner & Anthony S. Zannas & Alexande, 2019. "SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13659-4
    DOI: 10.1038/s41467-019-13659-4
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