ArticleeLife2019
Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting and insertion of tail-anchored proteins.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Retrograde trafficking inhibitors allosterically trap Get3 to block tail-anchored protein biogenesis.bioRxiv : the preprint server for biology · 2026Article
- Review
- Toward optimizing diversifying base editors for high-throughput mutational scanning studies.Nucleic acids research · 2025Article
- Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.PLoS genetics · 2025Article
- CRISPR screens and lectin microarrays identify high mannose N-glycan regulators.Nature communications · 2024Article
- From enhancers to genome conformation: complex transcriptional control underlies expression of a single herpesviral gene.bioRxiv : the preprint server for biology · 2024Article
- CRISPR screens and lectin microarrays identify novel high mannose N-glycan regulators.bioRxiv : the preprint server for biology · 2024Article
- Maximizing CRISPRi efficacy and accessibility with dual-sgRNA libraries and optimal effectors.eLife · 2022Article
- Structurally derived universal mechanism for the catalytic cycle of the tail-anchored targeting factor Get3.Nature structural & molecular biology · 2022Article
- Article
- Structural insights into metazoan pretargeting GET complexes.Nature structural & molecular biology · 2021Article
- Review
- Small Molecule Inhibitors Targeting the Interaction of Ricin Toxin A Subunit with Ribosomes.ACS infectious diseases · 2020Article
- The macrophage microtubule network acts as a key cellular controller of the intracellular fate of Leishmania infantum.PLoS neglected tropical diseases · 2020Article
- Targeting the Early Endosome-to-Golgi Transport of Shiga Toxins as a Therapeutic Strategy.Toxins · 2020Review
- Small Trafficking Inhibitor Retro-2 Disrupts the Microtubule-Dependent Trafficking of Autophagic Vacuoles.Frontiers in cell and developmental biology · 2020Article
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
The small molecule Retro-2 prevents ricin toxicity through a poorly-defined mechanism of action (MOA), which involves halting retrograde vesicle transport to the endoplasmic reticulum (ER). CRISPRi genetic interaction analysis revealed Retro-2 activity resembles disruption of the transmembrane domain recognition complex (TRC) pathway, which mediates post-translational ER-targeting and insertion of tail-anchored (TA) proteins, including SNAREs required for retrograde transport. Cell-based and in vitro assays show that Retro-2 blocks delivery of newly-synthesized TA-proteins to the ER-targeting factor ASNA1 (TRC40). An ASNA1 point mutant identified using CRISPR-mediated mutagenesis abolishes both the cytoprotective effect of Retro-2 against ricin and its inhibitory effect on ASNA1-mediated ER-targeting. Together, our work explains how Retro-2 prevents retrograde trafficking of toxins by inhibiting TA-protein targeting, describes a general CRISPR strategy for predicting the MOA of small molecules, and paves the way for drugging the TRC pathway to treat broad classes of viruses known to be inhibited by Retro-2.
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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.