ArticleThe Journal of biological chemistry2015
Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable Mutant Preprotein Cargos.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 31 citations in OpenAlex.
- Structural basis of signal peptide recognition by the signal peptidase complex.Nature communications · 2026Article
- Article
- Effect of Different Signal Peptides on the Expression of Glucoamylase fromJournal of fungi (Basel, Switzerland) · 2026Article
- Loss of Preproinsulin Interaction with Signal Recognition Particle Activates Protein Quality Control, Decreasing mRNA Stability.Journal of molecular biology · 2024Article
- Pathogenic signal peptide variants in the human genome.NAR genomics and bioinformatics · 2023Article
- Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation.The Journal of biological chemistry · 2022Article
- Take Me Home, Protein Roads: Structural Insights into Signal Peptide Interactions during ER Translocation.International journal of molecular sciences · 2021Review
- Spc1 regulates the signal peptidase-mediated processing of membrane proteins.Journal of cell science · 2021Article
- Comparative Multiplexed Interactomics of SARS-CoV-2 and Homologous Coronavirus Nonstructural Proteins Identifies Unique and Shared Host-Cell Dependencies.ACS infectious diseases · 2020Article
- IFN-γ treatment protocol for MHC-IJournal for immunotherapy of cancer · 2020Article
- Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies.bioRxiv : the preprint server for biology · 2020Article
- Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1.Nature cancer · 2020Article
- Defective endoplasmic reticulum export causes proinsulin misfolding in pancreatic β cells.Molecular and cellular endocrinology · 2019Article
- Splicing-Dependent Subcellular Targeting of Borna Disease Virus Nucleoprotein Isoforms.Journal of virology · 2019Article
- Plasmepsin V cleaves malaria effector proteins in a distinct endoplasmic reticulum translocation interactome for export to the erythrocyte.Nature microbiology · 2018Article
- Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins.The Journal of biological chemistry · 2018Article
- Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Upon translocation across the endoplasmic reticulum (ER) membrane, secretory proteins are proteolytically processed to remove their signal peptide by signal peptidase (SPase). This process is critical for subsequent folding, intracellular trafficking, and maturation of secretory proteins. Prokaryotic SPase has been shown to be a promising antibiotic target. In contrast, to date, no eukaryotic SPase inhibitors have been reported. Here we report that introducing a proline immediately following the natural signal peptide cleavage site not only blocks preprotein cleavage but also, in trans, impairs the processing and maturation of co-expressed preproteins in the ER. Specifically, we find that a variant preproinsulin, pPI-F25P, is translocated across the ER membrane, where it binds to the catalytic SPase subunit SEC11A, inhibiting SPase activity in a dose-dependent manner. Similar findings were obtained with an analogous variant of preproparathyroid hormone, demonstrating that inhibition of the SPase does not depend strictly on the sequence or structure of the downstream mature protein. We further show that inhibiting SPase in the ER impairs intracellular processing of viral polypeptides and their subsequent maturation. These observations suggest that eukaryotic SPases (including the human ortholog) are, in principle, suitable therapeutic targets for antiviral drug design.
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Registered trials
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.