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Deubiquitinating Enzymes Related to Autophagy: New Therapeutic Opportunities?


Deubiquitinating Enzymes Related to Autophagy: New Therapeutic Opportunities?

Anne-Claire Jacomin et al. Cells.


Autophagy is an evolutionary conserved catabolic process that allows for the degradation of intracellular components by lysosomes. This process can be triggered by nutrient deprivation, microbial infections or other challenges to promote cell survival under these stressed conditions. However, basal levels of autophagy are also crucial for the maintenance of proper cellular homeostasis by ensuring the selective removal of protein aggregates and dysfunctional organelles. A tight regulation of this process is essential for cellular survival and organismal health. Indeed, deregulation of autophagy is associated with a broad range of pathologies such as neuronal degeneration, inflammatory diseases, and cancer progression. Ubiquitination and deubiquitination of autophagy substrates, as well as components of the autophagic machinery, are critical regulatory mechanisms of autophagy. Here, we review the main evidence implicating deubiquitinating enzymes (DUBs) in the regulation of autophagy. We also discuss how they may constitute new therapeutic opportunities in the treatment of pathologies such as cancers, neurodegenerative diseases or infections.

Keywords: DUB; aggrephagy; autophagy; chaperone-mediated autophagy; deubiquitinating enzymes; inhibitor; mitophagy; small-molecule; ubiquitin; ubiquitin proteases.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
An overview of the macroautophagy process. Initiation of autophagy is under the control of sensor pathways that can sense the availability of nutrients, growth factors, insulin or other stresses. The main regulators of autophagy are AMPK (AMP-activated kinase) and mTORC1 (mTOR complex (1) which act as autophagy activator and inhibitor, respectively. AMPK and mTORC1 regulate the activation of the ULK1 complex which, together with the PI3K-Ш complex, initiates the autophagosome formation. The formation of an autophagosome starts with the generation of a phagophore which elongates into an isolation membrane where the cargos to be degraded are gathered. The enclosure of the isolation membrane forms a double-membraned autophagosome that matures and eventually fuses with the lysosome, forming an autolysosome where lysosomal hydrolases degrade its content. The Atg12 and LC3 conjugation systems are essential for the autophagy process and formation of the autophagosome. The Atg12 conjugation system consists in the formation of the Atg12-Atg5-Atg16L1 complex that then promotes the conjugation of LC3; pro-LC3 is cleaved by Atg4 (LC3-I) which is then conjugated with phosphatidylethanolamine (PE) (LC3-II) before being anchored to the nascent autophagosomal membrane.
Figure 2
Figure 2
Localization of the action of DUBs in the ubiquitination process. Ubiquitination is catalyzed by three types of enzymes: E1, E2, E3. It is a reversible reaction. DUBs process ubiquitin chains at three level: (A) For the generation of ubiquitin monomers from a ubiquitin precursor; (B) for the selective removal of ubiquitin moieties on ubiquitinated proteins; and (C) for the recycling of ubiquitin from protein degraded by the proteasome.
Figure 3
Figure 3
Functional roles of eukaryotic deubiquitinating enzymes in autophagy. (A) DEPTOR interacts with mTOR and inhibits its kinase activity. Under nutrient-rich conditions, DEPTOR is degraded continuously, and mTOR is active, promoting cell growth. However, under nutrient shortage, DEPTOR is stabilized by deubiquitination by OTUB1, interacts with mTOR and inhibits its kinase activity, allowing for the induction of autophagy. (B) The deubiquitination of ULK1 by USP20 allows for its stabilization and promotion of autophagy induction. (C) Beclin1 is an essential modulator of the PI3K-Ш complex. Beclin1 ubiquitination is crucial to its function. Deubiquitination by A20 inhibits Beclin1 activity by promoting its interaction with the inhibitor Bcl-2. USP14 negatively regulates Beclin1 activity. Other DUBs positively regulate autophagy by stabilizing Beclin1 (USP9X, USP10, USP13, USP19). The deubiquitination of RALB by USP33 benefits their interaction and the induction of autophagy. Ubiquitination also mediates the degradation of selected cargoes by autophagy. (D) The deubiquitination of α-synuclein aggregates by USP9X favor their degradation by autophagy, while UCH-L1 contribute to the accumulation of α-synuclein by downregulating its lysosomal degradation. The deubiquitination of various protein aggregates by ZRANB1 or USP36 impairs their degradation by autophagy. Invasion by intra-cellular bacteria tends to induce the accumulation of aggregate-like structures (ALIS) which are ubiquitinated and contribute to the induction of bacterial clearance by xenophagy; the DUB-like enzyme Ssel secreted by Salmonella deubiquitinates ALIS, resulting in a downregulation of autophagy and better survival of the bacteria. (E) Mitophagy selectively degrades mitochondria. USP8 promotes Parkin-mediated mitophagy by deubiquitinating Parkin and promoting its recruitment to the mitochondria. USP30, s-USP35, and USP15 counteract Parkin by deubiquitinating Parkin’s substrates, thus impairing mitophagy. (F) Specific ubiquitinated substrates can also be targeted for autophagy. Deubiquitination of HIF-1α and Connexin-43 (Cx43) by Cezanne and USP8, respectively, prevents their lysosomal degradation. (G) Autophagosomes can fuse with the endosomes. This fusion requires the ESCRT machinery as well as AMSH (AtAMSH1 in A. thaliana). USP20 and USP30 to a lesser extent favor the direction of the β2-adrenergic receptors to the autophagosome for degradation. In Drosophila, dUSP8 and dUSP12 positively regulate autophagy by contributing to the biogenesis of the lysosome. (H) Deubiquitination of H2B by USP44 negatively regulates the transcriptional activation of autophagy. Legend: Colored arrows show the action of DUBs that support (green) or inhibit (red) autophagy. Pink proteins are molecular inhibitors of autophagy; green proteins are inducers of autophagy.

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