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Статья
SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection
2021
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. © 2019, The Author(s).
Цитирование
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Версии
- 1. Version of Record от 2021-04-27
Метаданные
Название журнала
- Nature Communications
Том
- 10
Выпуск
- 1
Страницы
- -
Ключевые слова
- beclin 1; S phase kinase associated protein 2; beclin 1; BECN1 protein, human; S phase kinase associated protein; SKP2 protein, human; cell component; degradation; immune response; infectivity; inhibition; physiological response; protein; virus; animal cell; Article; autophagosome; autophagy; controlled study; flow cytometry; gene overexpression; genetic transfection; human; human cell; IC50; immunoprecipitation; Middle East respiratory syndrome; nonhuman; phenotype; prevalence; protein degradation; protein expression; protein phosphorylation; real time polymerase chain reaction; toxicity assay; ubiquitination; viral plaque assay; virus inhibition; virus replication; Western blotting; animal; autophagy; Chlorocebus aethiops; Coronavirus infection; drug effect; gene knockdown; genetics; HEK293 cell line; immunology; metabolism; Middle East respiratory syndrome coronavirus; pathogenicity; ubiquitination; Vero cell line; virology; Middle East; Coronavirus; Animals; Autophagy; Beclin-1; Chlorocebus aethiops; Coronavirus Infections; Gene Knockdown Techniques; HEK293 Cells; Humans; Middle East Respiratory Syndrome Coronavirus; Proteolysis; S-Phase Kinase-Associated Proteins; Ubiquitination; Vero Cells
Издатель
- Nature Research
Тип документа
- journal article
Тип лицензии Creative Commons
- CC
Правовой статус документа
- Свободная лицензия
Источник
- scopus
