1. The deubiquitinase USP11 is a versatile and conserved regulator of autophagy.
- Author
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Basic M, Hertel A, Bajdzienko J, Bonn F, Tellechea M, Stolz A, Kern A, Behl C, and Bremm A
- Subjects
- Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Animals, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins genetics, Cell Line, Gene Knockout Techniques, Humans, Peptide Fragments genetics, Peptide Fragments metabolism, Thiolester Hydrolases genetics, Autophagy, Caenorhabditis elegans enzymology, Caenorhabditis elegans Proteins metabolism, Thiolester Hydrolases metabolism
- Abstract
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., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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