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Bioactivatable inhibitor of ubiquitin-dependent proteasomal degradation

ABSTRACT: The hyperactive state of malignant cells results in the production of an excess of aberrant proteins that challenge the clearing capacity of the ubiquitin-proteasome system (UPS), resulting in an increased sensitivity towards drugs that reduce the efficacy of this critical proteolytic system. In this project we report the identification of an inhibitor that subsequent to cellular metabolism inhibits the UPS.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Rozbeh Jafari

LAB HEAD: Janne Lehtiö

PROVIDER: PXD019519 | Pride | 2021-11-03

REPOSITORIES: Pride

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			Action	DRS
	20161216_RJNDTA_LG_3hrs_CBK1.raw	Raw
	20161216_RJNDTA_LG_3hrs_CBK2.raw	Raw
	20161216_RJNDTA_LG_3hrs_CBK3.raw	Raw
	20161216_RJNDTA_LG_3hrs_DMSO1.raw	Raw
	20161216_RJNDTA_LG_3hrs_DMSO2.raw	Raw

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1 - 5 of 8

Publications

Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound.

Giovannucci Tatiana A TA Salomons Florian A FA Haraldsson Martin M Elfman Lotta H M LHM Wickström Malin M Young Patrick P Lundbäck Thomas T Eirich Jürgen J Altun Mikael M Jafari Rozbeh R Gustavsson Anna-Lena AL Johnsen John Inge JI Dantuma Nico P NP

Cell death & disease 20211006 10

Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-indep ...[more]

PMID: 34615851

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Variation in Ubiquitin System Genes Creates Substrate-Specific Effects on Proteasomal Protein Degradation

Project description:Ubiquitin-proteasome system (UPS) protein degradation regulates protein abundance and eliminates misfolded and damaged proteins from eukaryotic cells. Variation in UPS activity influences numerous cellular and organismal phenotypes. However, to what extent such variation results from individual genetic differences is almost entirely unknown. Here, we developed a statistically powerful mapping approach to characterize the genetic basis of variation in UPS activity. Using the yeast Saccharomyces cerevisiae, we systematically mapped genetic influences on the N-end rule, a UPS pathway that recognizes N-degrons, degradation-promoting signals in protein N-termini. We identified 149 genomic loci that influence UPS activity across the complete set of N-degrons. Resolving four loci to individual causal nucleotides identified regulatory and missense variants in ubiquitin system genes whose products process (NTA1), recognize (UBR1 and DOA10), and ubiquitinate (UBC6) cellular proteins. Each of these genes contained multiple causal variants and several individual variants had substrate-specific effects on UPS activity. A cis-acting promoter variant that modulates UPS activity by altering UBR1 expression also alters the abundance of 36 proteins without affecting levels of the corresponding mRNAs. Our results demonstrate that natural genetic variation shapes the full sequence of molecular events in protein ubiquitination and implicate genetic influences on the UPS as a prominent source of post-translational variation in gene expression.

2022-10-26 | GSE213689 | GEO

Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

Project description:Branched‐chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi‐omics analyses in Caenorhabditis elegans, we identified adaptive regulation of the ubiquitin‐proteasome system (UPS) in response to defective BCAA catabolic reactions after the initial transamination step. Worms with impaired BCAA metabolism show a slower turnover of a GFP‐based proteasome substrate, which is suppressed by loss‐of‐function of the first BCAA catabolic enzyme, the branched‐chain aminotransferase BCAT‐1. The exogenous supply of BCAA‐derived carboxylic acids, which are known to accumulate in the body fluid of patients with BCAA metabolic disorders, is sufficient to regulate the UPS. The link between BCAA intermediates and UPS function presented here sheds light on the unexplained role of BCAAs in the aging process and opens future possibilities for therapeutic interventions.

2022-09-22 | GSE185451 | GEO

Theileria parasites sequester host eIF5a to escape elimination by host-mediated autophagy

Project description:Intracellular pathogens develop elaborate mechanisms to survive within the hostile environments of host cells. Theileria parasites infect bovine leukocytes and cause devastating diseases in cattle in developing countries. Theileria spp. have evolved sophisticated strategies to hijack host leukocytes, inducing proliferative and invasive phenotypes characteristic of cell transformation. Intracellular Theileria parasites secrete proteins into the host cell and recruit host proteins to induce oncogenic signaling for parasite survival. It is unknown how Theileria parasites evade host cell defense mechanisms, such as autophagy, to survive within host cells. Here, we show that Theileria annulata parasites sequester the host eIF5a protein to their surface to escape elimination by autophagic processes. We identified a small-molecule compound that reduces parasite load by inducing autophagic flux in host leukocytes, thereby uncoupling Theileria parasite survival from host cell survival. We took a chemical genetics approach to show that this compound induced host autophagy mechanisms and the formation of autophagic structures via AMPK activation and the release of the host protein eIF5A which is sequestered at the parasite surface. The sequestration of host eIF5a to the parasite surface offers a strategy to escape elimination by autophagic mechanisms. These results show how intracellular pathogens can avoid host defense mechanisms and identify a new anti-Theileria drug that induces autophagy to target parasite removal.

2024-05-24 | PXD047937 | Pride

Dependence of Synaptic Protein Degradation on Proteasomal Function

Project description:Synaptic function crucially depends on uninterrupted synthesis and degradation of synaptic proteins. While much has been learned on synaptic protein synthesis, little is known on the routes by which synaptic proteins are degraded. Here we systematically studied how inhibition of the ubiquitin-proteasomal system (UPS) affects the degradation rates of thousands of neuronal and synaptic proteins. We identified a number of proteins, including several proteins related to glutamate receptor trafficking, whose degradation rates were significantly slowed by UPS inhibition. Unexpectedly, however, degradation rates of most synaptic proteins were not significantly affected. Interestingly, many of the differential effects of UPS inhibition were readily explained by a quantitative framework that considered known metabolic turnover rates for the same proteins. In contrast to the limited effects on protein degradation, UPS inhibition profoundly and preferentially suppressed the synthesis of a large number of synaptic proteins. Our findings point to the importance of the UPS in the degradation of certain synaptic proteins, yet indicate that under basal conditions most synaptic proteins might be degraded through alternative pathways.

2018-10-26 | PXD004813 | Pride

VCP D1 ATPase activation enhances both autophagic and proteasomal neurotoxic protein clearance

Project description:Autophagy upregulation enhances the clearance of various neurotoxic proteins and ameliorates their toxicities in disease models. Thus, autophagy activators may have therapeutic utility. Here, we have identified the essential protein VCP/p97 as a target of the autophagy-inducing molecule SMER28, providing a mechanism for a molecule that has shown promising results in animal models of neurodegeneration. SMER28 stimulates VCP D1 ATPase activity to activate autophagy by enhancing interactions of PI3K complex components to increase PI(3)P production and consequent autophagosome formation. Interestingly, SMER28-mediated increase in VCP D1 ATPase activity also enhances degradation of short-lived misfolded and aggregate-prone proteins through the ubiquitin-proteasome system (UPS). We further show that another recently described activator of VCP induces autophagy and UPS flux in a comparable manner, providing additional evidence that targeting VCP D1 ATPase domain could be a useful approach for clearance of aggregate-prone proteins by both autophagy-lysosome and proteasomal routes.

2022-07-15 | PXD027750 | Pride

Dependence of Synaptic Protein Degradation on Proteasomal Function -Part3

2018-10-26 | PXD004711 | Pride

Dependence of Synaptic Protein Degradation on Proteasomal Function -Part2

2018-10-26 | PXD004726 | Pride

VDAC2 ligands selectively and potently block BAK-mediated apoptosis to allow long-term clonogenic cell survival

Project description:This study aimed to characterise the protein that a novel compound binds to, thus promoting its ability to inhibit BAK apoptotic activity.

2019-10-11 | PXD013129 | Pride

Drug-target of DNA methyltransferase inhibitors

Project description:Malaria eradication requires the development of new drugs to combat drug-resistant parasites. The search for new chemical scaffolds that target novel pathways of the human malaria parasite Plasmodium falciparum is of highest priority. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus sp. (trilobine derivatives) as active in the nanomolar range against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivates allowed us to identify compound 84 (c-84) that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35-88nM). Efforts were made to obtain compounds with significantly improved preclinical properties. Out of those, compound 125 (c-125) delays the onset of parasitemia in P. berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays) and in vivo using membrane feeding assay in the Anopheles stephensi vector. C-125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, we used a chemical pull-down to identify potential protein targets of this chemical family. Our mass spectrometry analysis identified the parasite interactome with trilobine alkaloid, allowing us to identify protein partners belonging to metabolic pathways that have not been previously targeted by antimalarial drugs or implicated in drug-resistance mechanisms in malaria parasites.

2023-01-01 | PXD036288 | Pride

RNA-Seq of A375 cells treated with tetracycline-based crosslinking probes, with and without competition by parent tetracyclines, to show specific binding of the tetracycline analogs Col-3 and doxycycline on rRNA substructures of the human ribosome

Project description:Upon finding that the tetracyclines COL-3 and doxycycline target unique rRNA substructures of the 80S ribosome (E-MTAB-7147), we confirmed these putative ribosomal binding sites by showing that tetracycline-based crosslinking probes are specifically competed from these rRNA structures by their parent drugs. In short, we incorporated dual bioorthogonal handles into tetracycline-based probes, containing both a photoactive diazirine to enable direct probe crosslinking to the human ribosome and an azide handle to allow selective enrichment of crosslinked biomolecules via copper-free ‘click’ chemistry. The COL-3 and doxycycline probes were each incubated with A375 cells, followed by irradiation at 365 nm to induce photolysis of the diazirine moiety and subsequent crosslinking to adjacent ribosomal components. Pulldown and RNA-Seq of the crosslinked RNAs from our experiments were used to identify enrichment of reverse transcription (RT) stops at ribosomal RNA sites caused by local crosslinking of our probes. In these experiments, UV crosslinking was preformed with the COL-3 and doxycycline probe compounds in the presence and absence of free COL-3 and doxycycline (i.e., parent tetracycline molecules lacking the bifunctional diazirine-azide moiety), which were used as competitors to specifically diminish crosslinking to the ribosomal RNA. Crosslinking to ribosomal RNA was determined using RNA-Seq based RT stop enrichment, which was was also compared to inactive tetracycline probes containing a modified bifunctional linker, a non-specific aniline probe, and untreated controls.

2018-08-31 | E-MTAB-7161 | biostudies-arrayexpress

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