The deubiquitinase USP11 is a versatile and conserved regulator of autophagy
| Autor: | Justyna Bajdzienko, Andreas Kern, Mila Basic, Alexandra Hertel, Mariana Tellechea, Alexandra Stolz, Florian Bonn, Christian Behl, Anja Bremm |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
autophagy
hAβ42 human amyloid-β protein 1 to 42 Lipid kinase activity PI(3)P phosphatidylinositol-3-phosphate mTORC1 Biochemistry Cell Line Gene Knockout Techniques chemistry.chemical_compound ubiquitin Animals Humans ULK1 unc-51-like autophagy activating kinase 1 WIPI WD-repeat domain phosphoinositide-interacting protein PI3KC3-C1 Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Mechanistic target of rapamycin USP11 ubiquitin-specific protease 11 proteostasis Amyloid beta-Peptides S6K S6 kinase biology Phosphatidylinositol 3-phosphate Autophagy DUB deubiquitinase LFQ label-free quantification IP immunoprecipitation NHT nonhuman targeting PI3KC3-C1 class III phosphatidylinositol 3-kinase complex I Cell Biology ACN acetonitrile Aβ amyloid-β NRBF2 nuclear receptor-binding factor 2 Peptide Fragments Cell biology deubiquitinase (DUB) Proteostasis chemistry Proteotoxicity mTORC1 mechanistic target of rapamycin complex 1 biology.protein Autophagy-Related Protein-1 Homolog BSA bovine serum albumin Thiolester Hydrolases Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.101263 |
| Popis: | Autophagy is a major cellular quality control system responsible for the degradation of proteins and organelles in response to stress and damage to maintain homeostasis. Ubiquitination of autophagy-related proteins or regulatory components is important for the precise control of autophagy pathways. Here, we show that the deubiquitinase ubiquitin-specific protease 11 (USP11) restricts autophagy and that KO of USP11 in mammalian cells results in elevated autophagic flux. We also demonstrate that depletion of the USP11 homolog H34C03.2 in Caenorhabditis elegans triggers hyperactivation of autophagy and protects the animals against human amyloid-β peptide 42 aggregation-induced paralysis. USP11 coprecipitated with autophagy-specific class III phosphatidylinositol 3-kinase complex I and limited its interaction with nuclear receptor-binding factor 2, thus decreasing lipid kinase activity of class III phosphatidylinositol 3-kinase complex I and subsequent recruitment of effectors such as WD-repeat domain phosphoinositide-interacting proteins to the autophagosomal membrane. Accordingly, more WD-repeat domain phosphoinositide-interacting protein 2 puncta accumulated in USP11 KO cells. In addition, USP11 interacts with and stabilizes the serine/threonine kinase mechanistic target of rapamycin, thereby further contributing to the regulation of autophagy induction. Taken together, our data suggested that USP11 impinges on the autophagy pathway at multiple sites and that inhibiting USP11 alleviates symptoms of proteotoxicity, which is a major hallmark of neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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