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

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 prote...

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Autores principales: Gassen, Nils C., Niemeyer, Daniela, Muth, Doreen, Corman, Victor M., Martinelli, Silvia, Gassen, Alwine, Hafner, Kathrin, Papies, Jan, Mösbauer, Kirstin, Zellner, Andreas, Zannas, Anthony S., Herrmann, Alexander, Holsboer, Florian, Brack-Werner, Ruth, Boshart, Michael, Müller-Myhsok, Bertram, Drosten, Christian, Müller, Marcel A., Rein, Theo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920372/
https://www.ncbi.nlm.nih.gov/pubmed/31852899
http://dx.doi.org/10.1038/s41467-019-13659-4
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author Gassen, Nils C.
Niemeyer, Daniela
Muth, Doreen
Corman, Victor M.
Martinelli, Silvia
Gassen, Alwine
Hafner, Kathrin
Papies, Jan
Mösbauer, Kirstin
Zellner, Andreas
Zannas, Anthony S.
Herrmann, Alexander
Holsboer, Florian
Brack-Werner, Ruth
Boshart, Michael
Müller-Myhsok, Bertram
Drosten, Christian
Müller, Marcel A.
Rein, Theo
author_facet Gassen, Nils C.
Niemeyer, Daniela
Muth, Doreen
Corman, Victor M.
Martinelli, Silvia
Gassen, Alwine
Hafner, Kathrin
Papies, Jan
Mösbauer, Kirstin
Zellner, Andreas
Zannas, Anthony S.
Herrmann, Alexander
Holsboer, Florian
Brack-Werner, Ruth
Boshart, Michael
Müller-Myhsok, Bertram
Drosten, Christian
Müller, Marcel A.
Rein, Theo
author_sort Gassen, Nils C.
collection PubMed
description 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.
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spelling pubmed-69203722019-12-20 SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection Gassen, Nils C. Niemeyer, Daniela Muth, Doreen Corman, Victor M. Martinelli, Silvia Gassen, Alwine Hafner, Kathrin Papies, Jan Mösbauer, Kirstin Zellner, Andreas Zannas, Anthony S. Herrmann, Alexander Holsboer, Florian Brack-Werner, Ruth Boshart, Michael Müller-Myhsok, Bertram Drosten, Christian Müller, Marcel A. Rein, Theo Nat Commun Article 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. Nature Publishing Group UK 2019-12-18 /pmc/articles/PMC6920372/ /pubmed/31852899 http://dx.doi.org/10.1038/s41467-019-13659-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gassen, Nils C.
Niemeyer, Daniela
Muth, Doreen
Corman, Victor M.
Martinelli, Silvia
Gassen, Alwine
Hafner, Kathrin
Papies, Jan
Mösbauer, Kirstin
Zellner, Andreas
Zannas, Anthony S.
Herrmann, Alexander
Holsboer, Florian
Brack-Werner, Ruth
Boshart, Michael
Müller-Myhsok, Bertram
Drosten, Christian
Müller, Marcel A.
Rein, Theo
SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
title SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
title_full SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
title_fullStr SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
title_full_unstemmed SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
title_short SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
title_sort skp2 attenuates autophagy through beclin1-ubiquitination and its inhibition reduces mers-coronavirus infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920372/
https://www.ncbi.nlm.nih.gov/pubmed/31852899
http://dx.doi.org/10.1038/s41467-019-13659-4
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