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. Here, Gassen et al . show that S-phase kinase-associated protein 2 (SKP2) is responsible for lysine-48-linked poly-ubiquitination of beclin 1, resulting in its proteasomal degradation, and that inhibition of SKP2 enhances autophagy and reduces replication of MERS coronavirus.
【저자키워드】 antivirals, Macroautophagy, Ubiquitin ligases, 【초록키워드】 AKT1, MERS-CoV, autophagy, antiviral drug, Replication, Protein, Phosphorylation, virus infection, Degradation, cellular, Middle East, Lysosomes, Skp2, MERS coronavirus, autophagic flux, respiratory syndrome coronavirus, E3 ligase, pharmacological, block, proteasomal degradation, BECN1, decrease, ENhance, responsible, resulting, reduced, regulated, reduce, conditions, affecting, other disease, PHLPP, 【제목키워드】 Infection, autophagy, Skp2, reduce, attenuate,