Fig. 9: Some potential SKP2 inhibitors affect autophagy and viral replication. | Nature Communications

Fig. 9: Some potential SKP2 inhibitors affect autophagy and viral replication.

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

Fig. 9

a VeroB4 cells were treated with various FDA-approved drugs (for abbreviations and concentrations see Supplementary Table 3) and cotreatment with Bafilomycin A1 (0.1 μM) was performed to evaluate the autophagic flux. The graph provides the means + SEM of three independent experiments, representative western blots are shown in Supplementary Fig. 8b. b VeroB4 cells were infected with MERS-CoV (MOI = 0.001), treated with the indicated drugs, and MERS-CoV genome copies were determined by RT-PCR 24 h and 48 h p.i.; data are presented as (log10) fold difference in relation to the DMSO control. Unprocessed data and PFU results are presented in Supplementary Fig. 9a–c. c Concentration-dependent inhibition of MERS-CoV replication by the SKP2-inhibitor (SKP2i), valinomycin (VAL) und niclosamide (NIC). VeroB4 cells were infected with MERS-CoV (MOI = 0.001) and treated with drug. MERS-CoV genome copies were determined by real-time RT-PCR at 48 h p.i., data present the percentage of remaining MERS-CoV genomes in comparison to vehicle treatment. In all panels, error bars denote the standard error of the mean, derived from n = 3 or n = 6 (c, no drug condition) biologically independent experiments. **p < 0.01, ***p < 0.001 (two-way ANOVA in a, one-way ANOVA in b, details in Supplementary Table 1). d Summary scheme: SKP2 leads to K48-linked poly-ubiquitination and thus degradation of BECN1. The effect of SKP2 can be diminished in two ways, either by chemical inhibition or by FKBP51, which scaffolds protein interactions ultimately leading to SKP2 inactivation through inhibiting its phosphorylation. Both scenarios enhance autophagy, which involves ATG14 oligomerization (probably 7–8mers) as recently described essential step in functional autophagy6. MERS-CoV reduces autophagy through distinct viral proteins leading to blockade of autophagosome-lysosome fusion and ATG14 oligomerization. Compounds inhibiting SKP2 reinstate autophagy and efficiently reduce viral production. Source data are provided as a Source Data file.

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