ArticleThe Biochemical journal2021
Mycolactone enhances the Ca2+ leak from endoplasmic reticulum by trapping Sec61 translocons in a Ca2+ permeable state.
Article in The Biochemical journal, 2021. 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, 19 citations in OpenAlex.
- Aberrant stromal tissue factor localisation and mycolactone-driven vascular dysfunction, exacerbated by IL-1β, are linked to fibrin formation in Buruli ulcer lesions.PLoS pathogens · 2022Trial
- A mycobacterial Sec61 inhibitor disrupts lysosome function by blocking Vacuolar-ATPase biosynthesis.European journal of cell biology · 2026Article
- Buruli ulcer.Nature reviews. Disease primers · 2025Review
- Toward Understanding the Mechanism of Client-Selective Small Molecule Inhibitors of the Sec61 Translocon.Journal of molecular recognition : JMR · 2025Review
- Disrupted Endoplasmic Reticulum CaBiology · 2024Review
- Signal peptide mimicry primes Sec61 for client-selective inhibition.Nature chemical biology · 2023Article
- A common mechanism of Sec61 translocon inhibition by small molecules.Nature chemical biology · 2023Article
- Review
- Kinetics of the thapsigargin-induced CaFrontiers in physiology · 2023Article
- Editorial: The evolving picture of CaFrontiers in physiology · 2023Article
- Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells.PLoS neglected tropical diseases · 2022Article
- Synthesis, Biological Evaluation and Docking Studies of Ring-Opened Analogues of Ipomoeassin F.Molecules (Basel, Switzerland) · 2022Article
- Sec61 complex/translocon: The role of an atypical ER CaFrontiers in physiology · 2022Review
- Antagonizing Sec62 function in intracellular CaFrontiers in physiology · 2022Article
- Signal Peptide Features Determining the Substrate Specificities of Targeting and Translocation Components in Human ER Protein Import.Frontiers in physiology · 2022Review
- The One That Got Away: How Macrophage-Derived IL-1β Escapes the Mycolactone-Dependent Sec61 Blockade in Buruli Ulcer.Frontiers in immunology · 2021Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
The Mycobacterium ulcerans exotoxin, mycolactone, is an inhibitor of co-translational translocation via the Sec61 complex. Mycolactone has previously been shown to bind to, and alter the structure of the major translocon subunit Sec61α, and change its interaction with ribosome nascent chain complexes. In addition to its function in protein translocation into the ER, Sec61 also plays a key role in cellular Ca2+ homeostasis, acting as a leak channel between the endoplasmic reticulum (ER) and cytosol. Here, we have analysed the effect of mycolactone on cytosolic and ER Ca2+ levels using compartment-specific sensors. We also used molecular docking analysis to explore potential interaction sites for mycolactone on translocons in various states. These results show that mycolactone enhances the leak of Ca2+ ions via the Sec61 translocon, resulting in a slow but substantial depletion of ER Ca2+. This leak was dependent on mycolactone binding to Sec61α because resistance mutations in this protein completely ablated the increase. Molecular docking supports the existence of a mycolactone-binding transient inhibited state preceding translocation and suggests mycolactone may also bind Sec61α in its idle state. We propose that delayed ribosomal release after translation termination and/or translocon 'breathing' during rapid transitions between the idle and intermediate-inhibited states allow for transient Ca2+ leak, and mycolactone's stabilisation of the latter underpins the phenotype observed.
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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.