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

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-F732-C Version Permalink: http://hdl.handle.net/21.11116/0000-0005-F733-B
Genre: Journal Article

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 Creators:
Gassen, Nils C.1, 2, Author              
Niemeyer, Daniela3, Author
Muth, Doreen3, Author
Corman, Victor M.3, Author
Martinelli, Silvia1, Author              
Gassen, Alwine3, Author
Hafner, Kathrin1, 2, Author              
Papies, Jan3, Author
Moesbauer, Kirstin3, Author
Zellner, Andreas1, Author              
Zannas, Anthony S.1, Author              
Herrmann, Alexander3, Author
Holsboer, Florian4, 5, 6, Author              
Brack-Werner, Ruth3, Author
Boshart, Michael3, Author
Mueller-Myhsok, Bertram1, 7, 8, Author              
Drosten, Christian3, Author
Mueller, Marcel A.3, Author
Rein, Theo1, 2, Author              
Affiliations:
1Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
2AG Rein, Theo, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society, ou_1607155              
3external, ou_persistent22              
4Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              
5Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              
6Emeritiertes wissenschaftliches Mitglied, Max Planck Institute of Psychiatry, Max Planck Society, ou_2074301              
7RG Müller-Myhsok, Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2040288              
8RG Statistical Genetics, Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2040288              

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 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.

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 Dates: 2019-12-18
 Publication Status: Published online
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Title: NATURE COMMUNICATIONS
Source Genre: Journal
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Pages: - Volume / Issue: 10 Sequence Number: 5770 Start / End Page: - Identifier: ISSN: 2041-1723