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

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, Alexander Herrmann, Florian Holsboer, Ruth Brack-Werner, Michael Boshart, Bertram Müller-Myhsok, Christian Drosten, Marcel A. Müller and Theo Rein ()
Additional contact information
Nils C. Gassen: Max Planck Institute of Psychiatry
Daniela Niemeyer: Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Doreen Muth: Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Victor M. Corman: Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
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
Kirstin Mösbauer: Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Andreas Zellner: Max Planck Institute of Psychiatry
Anthony S. Zannas: Max Planck Institute of Psychiatry
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
Christian Drosten: Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Marcel A. Müller: Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Theo Rein: Max Planck Institute of Psychiatry

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13659-4

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