1. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection.
- Author
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Gassen NC, Niemeyer D, Muth D, Corman VM, Martinelli S, Gassen A, Hafner K, Papies J, Mösbauer K, Zellner A, Zannas AS, Herrmann A, Holsboer F, Brack-Werner R, Boshart M, Müller-Myhsok B, Drosten C, Müller MA, and Rein T
- Subjects
- Animals, Autophagy drug effects, Chlorocebus aethiops, Coronavirus Infections virology, Gene Knockdown Techniques, HEK293 Cells, Humans, Middle East Respiratory Syndrome Coronavirus pathogenicity, Proteolysis drug effects, S-Phase Kinase-Associated Proteins antagonists & inhibitors, S-Phase Kinase-Associated Proteins genetics, Ubiquitination drug effects, Ubiquitination immunology, Vero Cells, Autophagy immunology, Beclin-1 metabolism, Coronavirus Infections immunology, Middle East Respiratory Syndrome Coronavirus immunology, S-Phase Kinase-Associated Proteins metabolism
- 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.
- Published
- 2019
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