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Journal Article

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

MPS-Authors
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Gassen,  Nils C.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
AG Rein, Theo, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society;

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Martinelli,  Silvia
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Hafner,  Kathrin
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
AG Rein, Theo, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society;

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Zellner,  Andreas
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Zannas,  Anthony S.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Holsboer,  Florian
Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;
Emeritiertes wissenschaftliches Mitglied, Max Planck Institute of Psychiatry, Max Planck Society;

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Mueller-Myhsok,  Bertram
RG Müller-Myhsok, Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
RG Statistical Genetics, Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Rein,  Theo
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
AG Rein, Theo, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Gassen, N. C., Niemeyer, D., Muth, D., Corman, V. M., Martinelli, S., Gassen, A., et al. (2019). SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. NATURE COMMUNICATIONS, 10: 5770. doi:10.1038/s41467-019-13659-4.


Abstract
Autophagy is an essential cellular process affecting virus infections and other diseases and Beclinl (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.