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The deubiquitinase USP11 is a versatile and conserved regulator of autophagy.

ABSTRACT: Autophagy is a major cellular quality control system responsible for degradation of proteins and organelles in response to stress and damage in order 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 USP11 restricts autophagy and that knockout (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 β-amyloid peptide 42 aggregation-induced paralysis. USP11 co-precipitated with the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) and limited its interaction with nuclear receptor-binding factor 2 (NRBF2), thus decreasing lipid kinase activity of the PI3KC3-C1 and subsequent recruitment of effectors like WIPI proteins to the autophagosomal membrane. Accordingly, more WIPI2-puncta accumulated in USP11 KO cells. In addition, USP11 interacts with and stabilizes the serine/threonine kinase mTOR, 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.

SUBMITTER: Basic M

PROVIDER: S-EPMC8546420 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Versatile regulation of autophagy by the deubiquitinase USP11

Project description:Ubiquitination is a versatile post-translational modification known to regulate autophagy. Here, we show that loss of the deubiquitinase USP11 leads to an increase in the autophagic flux. To investigate the molecular details of how USP11 impacts autophagy, we determined interaction partners of USP11 using an affinity purification-mass spectrometry approach. GFP-tagged, catalytically inactive USP11(C318S) was overexpressed in 293 cells. After 4 hour treatment with Torin 1, an inhibitor of mTOR that induces autophagy, cells were lysed and samples further processed for analysis. Catalytically inactive USP11 was used to increase the chances of capturing both interaction partners and potential substrates. We identified many autophagy-related proteins that co-precipitated with USP11, suggesting that USP11 does not regulate autophagy via a single substrate, but that the observed phenotype is the sum of many interactions, each of which should be independently investigated in more detail. Our work focused on elucidating the regulation of autophagy via the lipid kinase complex PI3KC3 complex I, as one of its components (VPS15) was identified in our USP11 interactome data. PI3KC3 complex I is crucial for initiation of autophagosome formation at the endoplasmatic reticulum. USP11 knockout caused an increase in complex activity, which could explain enhanced autophagy in these cells.

2022-02-16 | PXD022143 | Pride

The deubiquitinase USP11 promotes ovarian cancer chemoresistance by stabilizing BIP.

Project description: Not available

| S-EPMC8277857 | biostudies-literature

USP11 degrades KLF4 via its deubiquitinase activity in liver diseases.

Project description:Krüppel-like factor 4 (KLF4) is a zinc-finger containing DNA-binding transcription factor involved in tumorigenesis and acts as a tumour suppressor or an oncogene depending on the tissue. In hepatocellular carcinoma (HCC), KLF4 has been considered as a tumour suppressor, although the mechanism underlying its action remains largely unknown. In this study, we identified the ubiquitin-specific peptidase USP11 as a KLF4-interacting deubiquitinating enzyme using a proteomic approach. USP11 destabilizes KLF4 through the removal of K63-dependent polyubiquitination, thereby inhibiting KLF4 expression. We also provide mechanistic insights into KLF4 degradation and show that USP11 depletion inhibits growth and chemoresistance of HCC cells by enhancing KLF4 stability. Importantly, lipid content was reduced and genes involved in fatty acid metabolism were down-regulated in an in vitro steatosis conditions upon USP11 knockout. Finally, elevated USP11 and reduced KLF4 levels were detected both in a hepatic steatosis in vitro model and in public clinical data of non-alcoholic fatty liver disease and HCC patients. Collectively, these findings suggest that USP11, as KLF4-binding partner, is an important mediator of hepatic tumorigenesis that functions via degradation of KLF4 and is a potential treatment target for liver diseases.

| S-EPMC8278108 | biostudies-literature

USP11 acts as a histone deubiquitinase functioning in chromatin reorganization during DNA repair.

Project description:How chromatin dynamics is regulated to ensure efficient DNA repair remains to be understood. Here, we report that the ubiquitin-specific protease USP11 acts as a histone deubiquitinase to catalyze H2AK119 and H2BK120 deubiquitination. We showed that USP11 is physically associated with the chromatin remodeling NuRD complex and functionally involved in DNA repair process. We demonstrated that USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and reorganization of the chromatin structure. As such, USP11 is involved in chromatin condensation, genomic stability, and cell survival. Together, these observations indicate that USP11 is a chromatin modifier critically involved in DNA damage response and the maintenance of genomic stability.

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Discovery of peptide ligands targeting a specific ubiquitin-like domain-binding site in the deubiquitinase USP11.

Project description:Ubiquitin-specific proteases (USPs) reverse ubiquitination and regulate virtually all cellular processes. Defined noncatalytic domains in USP4 and USP15 are known to interact with E3 ligases and substrate recruitment factors. No such interactions have been reported for these domains in the paralog USP11, a key regulator of DNA double-strand break repair by homologous recombination. We hypothesized that USP11 domains adjacent to its protease domain harbor unique peptide-binding sites. Here, using a next-generation phage display (NGPD) strategy, combining phage display library screening with next-generation sequencing, we discovered unique USP11-interacting peptide motifs. Isothermal titration calorimetry disclosed that the highest affinity peptides (KD of ∼10 μm) exhibit exclusive selectivity for USP11 over USP4 and USP15 in vitro Furthermore, a crystal structure of a USP11-peptide complex revealed a previously unknown binding site in USP11's noncatalytic ubiquitin-like (UBL) region. This site interacted with a helical motif and is absent in USP4 and USP15. Reporter assays using USP11-WT versus a binding pocket-deficient double mutant disclosed that this binding site modulates USP11's function in homologous recombination-mediated DNA repair. The highest affinity USP11 peptide binder fused to a cellular delivery sequence induced significant nuclear localization and cell cycle arrest in S phase, affecting the viability of different mammalian cell lines. The USP11 peptide ligands and the paralog-specific functional site in USP11 identified here provide a framework for the development of new biochemical tools and therapeutic agents. We propose that an NGPD-based strategy for identifying interacting peptides may be applied also to other cellular targets.

| S-EPMC6333900 | biostudies-literature

USP11: A key regulator of cIAP2 stability and sensitivity to SMAC mimetics.

Project description:The critical function of cellular inhibitor of apoptosis proteins (cIAPs) in the protection of cancer cells from numerous apoptotic stimuli prompted the development of second mitochondria-derived activator of caspases (SMAC) mimetics. We recently addressed a novel survival pathway in which cIAP2 is induced by tumor necrosis factor-α and is stabilized by its specific deubiquitylase, USP11, rendering cells resistant to SMAC mimetics.

| S-EPMC4909448 | biostudies-other

USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1.

Project description:Spinal cord ischemia-reperfusion injury (SCIRI) is a serious trauma that can lead to loss of sensory and motor function. Ferroptosis is a new form of regulatory cell death characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis has been studied in various diseases; however, the exact function and molecular mechanism of ferroptosis in SCIRI remain unknown. In this study, we demonstrated that ferroptosis is involved in the pathological mechanism of SCIRI. Inhibition of ferroptosis could promote the recovery of motor function in mice after SCIRI. In addition, we found that ubiquitin-specific protease 11 (USP11) was significantly upregulated in neuronal cells after hypoxia-reoxygenation and in the spinal cord in mice with I/R injury. Knockdown of USP11 in vitro and KO of USP11 in vivo (USP11-/Y) significantly decreased neuronal cell ferroptosis. In mice, this promotes functional recovery after SCIRI. In contrast, in vitro, USP11 overexpression leads to classic ferroptosis events. Overexpression of USP11 in mice resulted in increased ferroptosis and poor functional recovery after SCIRI. Interestingly, upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux, a potential mechanism through which USP11 may enhance ferroptosis. The decreased autophagy markedly weakened the ferroptosis mediated by USP11 and autophagy induction had a synergistic effect with USP11. Importantly, USP11 promotes autophagy activation by stabilizing Beclin 1, thereby leading to ferroptosis. In conclusion, this study shows that ferroptosis is closely associated with SCIRI, and that USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of SCIRI.

| S-EPMC9177661 | biostudies-literature

The Salmonella deubiquitinase SseL inhibits selective autophagy of cytosolic aggregates.

Project description:Cell stress and infection promote the formation of ubiquitinated aggregates in both non-immune and immune cells. These structures are recognised by the autophagy receptor p62/sequestosome 1 and are substrates for selective autophagy. The intracellular growth of Salmonella enterica occurs in a membranous compartment, the Salmonella-containing vacuole (SCV), and is dependent on effectors translocated to the host cytoplasm by the Salmonella pathogenicity island-2 (SPI-2) encoded type III secretion system (T3SS). Here, we show that bacterial replication is accompanied by the formation of ubiquitinated structures in infected cells. Analysis of bacterial strains carrying mutations in genes encoding SPI-2 T3SS effectors revealed that in epithelial cells, formation of these ubiquitinated structures is dependent on SPI-2 T3SS effector translocation, but is counteracted by the SPI-2 T3SS deubiquitinase SseL. In macrophages, both SPI-2 T3SS-dependent aggregates and aggresome-like induced structures (ALIS) are deubiquitinated by SseL. In the absence of SseL activity, ubiquitinated structures are recognized by the autophagy receptor p62, which recruits LC3 and targets them for autophagic degradation. We found that SseL activity lowers autophagic flux and favours intracellular Salmonella replication. Our data therefore show that there is a host selective autophagy response to intracellular Salmonella infection, which is counteracted by the deubiquitinase SseL.

| S-EPMC3375275 | biostudies-literature

Epigenetics as a versatile regulator of fibrosis.

Project description:Fibrosis, a process caused by excessive deposition of extracellular matrix (ECM), is a common cause and outcome of organ failure and even death. Researchers have made many efforts to understand the mechanism of fibrogenesis and to develop therapeutic strategies; yet, the outcome remains unsatisfactory. In recent years, advances in epigenetics, including chromatin remodeling, histone modification, DNA methylation, and noncoding RNA (ncRNA), have provided more insights into the fibrotic process and have suggested the possibility of novel therapy for organ fibrosis. In this review, we summarize the current research on the epigenetic mechanisms involved in organ fibrosis and their possible clinical applications.

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The ubiquitin-specific protease USP36 is a conserved histone H2B deubiquitinase.

Project description:Histone H2B monoubiquitination plays a critical role in the regulation of gene transcription. Deregulation of H2B monoubiquitination contributes to human pathologies, such as cancer. Here we report that human USP36 is a novel H2Bub1 deubiquitinase. We show that USP36 interacts with H2B and deubiquitinates H2Bub1 in cells and in vitro. Overexpression of USP36 markedly reduced the levels of H2Bub1 in cells. Using the p21 gene as a model, we demonstrate that depletion of USP36 increases H2Bub1 at the p21 locus, primarily within its gene body. Consistently, knockdown of USP36 induced the expression of p21 and inhibits cell proliferation. Together, our results reveal USP36 as a novel H2B deubiquitinase and shed light on its additional functions in regulating gene expression.

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