ArticleJournal of cellular and molecular medicine2015
Thiostrepton interacts covalently with Rpt subunits of the 19S proteasome and proteasome substrates.
Article in Journal of cellular and molecular medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- The Regulatory Network of FOXM1: Orchestrating Cancer Progression and Resistance to Therapy.International journal of molecular sciences · 2026Review
- Mechanism-based peroxiredoxin 3 inhibitors exploit a covalent warhead for cancer therapy.Science advances · 2025Article
- Inhibition of proteolytic and ATPase activities of the proteasome by the BTK inhibitor CGI-1746.iScience · 2024Article
- Injury-induced Foxm1 expression in the mouse kidney drives epithelial proliferation by a cyclin F-dependent mechanism.JCI insight · 2024Article
- Normal Proteasome Function Is Needed to Prevent Kidney Graft Injury during Cold Storage Followed by Transplantation.International journal of molecular sciences · 2024Article
- Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity.BMC cancer · 2021Article
- Dehydropeptide Supramolecular Hydrogels and Nanostructures as Potential Peptidomimetic Biomedical Materials.International journal of molecular sciences · 2021Review
- Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy.ACS chemical biology · 2020Article
- A preclinical evaluation of thiostrepton, a natural antibiotic, in nasopharyngeal carcinoma.Investigational new drugs · 2020Article
- Biological Evaluation of Naproxen-Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors.Pharmaceutics · 2020Article
- Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation.Scientific reports · 2019Article
- YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function.Chemical reviews · 2017Review
- Thiostrepton Variants Containing a Contracted Quinaldic Acid Macrocycle Result from Mutagenesis of the Second Residue.ACS chemical biology · 2016Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Here, we report a novel mechanism of proteasome inhibition mediated by Thiostrepton (Thsp), which interacts covalently with Rpt subunits of the 19S proteasome and proteasome substrates. We identified Thsp in a cell-based high-throughput screen using a fluorescent reporter sensitive to degradation by the ubiquitin-proteasome pathway. Thiostrepton behaves as a proteasome inhibitor in several paradigms, including cell-based reporters, detection of global ubiquitination status, and proteasome-mediated labile protein degradation. In vitro, Thsp does not block the chymotrypsin activity of the 26S proteasome. In a cell-based IκBα degradation assay, Thsp is a slow inhibitor and 4 hrs of treatment achieves the same effects as MG-132 at 30 min. We show that Thsp forms covalent adducts with proteins in human cells and demonstrate their nature by mass spectrometry. Furthermore, the ability of Thsp to interact covalently with the cysteine residues is essential for its proteasome inhibitory function. We further show that a Thsp modified peptide cannot be degraded by proteasomes in vitro. Importantly, we demonstrate that Thsp binds covalently to Rpt subunits of the 19S regulatory particle and forms bridges with a proteasome substrate. Taken together, our results uncover an important role of Thsp in 19S proteasome inhibition.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.