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Gassen, N.C.* ; Niemeyer, D.* ; Corman, V.M.* ; Martinelli, S.* ; Gassen, A.* ; Hafner, K.* ; Papies, J.* ; Mösbauer, K.* ; Zellner, A.* ; Zannas, A.S.* ; Herrmann, A. ; Holsboer, F.* ; Brack-Werner, R. ; Boshart, M.* ; Müller-Myhsok, B.* ; Drosten, C.* ; Müller, M.A.* ; Rein, T.*

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

Nat. Commun. 10:5770 (2019)
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Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Small-molecule Inhibitors; Beclin 1; Regulates Autophagy; Mammalian Autophagy; Reverse Genetics; Sindbis Virus; Protein; Replication; Binding; Fkbp51
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 10, Issue: 1, Pages: , Article Number: 5770 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed