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, Moesbauer, Kirstin, Zellner, Andreas
et al (show 9 more authors) (2019) SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. NATURE COMMUNICATIONS, 10.

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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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 23 Jan 2020 09:30
Last Modified: 19 Jan 2022 21:10
DOI: 10.1038/s41467-019-13659-4
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3071627