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Synthesis of 20-Membered Macrocyclic Pseudo-Natural Products Yields Inducers of LC3 Lipidation
Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, Germany; Technical University Dortmund, Faculty of Chemistry, Chemical Biology, Otto-Hahn-Strasse 6, Dortmund, Germany.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Max Planck Institute of Molecular Physiology, Crystallography and Biophysics Unit, Otto-Hahn-Strasse 11, Dortmund, Germany.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0001-7930-0134
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2022 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 61, no 11, article id e202114328Article in journal (Refereed) Published
Abstract [en]

Design and synthesis of pseudo-natural products (PNPs) through recombination of natural product (NP) fragments in unprecedented arrangements enables the discovery of novel biologically relevant chemical matter. With a view to wider coverage of NP-inspired chemical and biological space, we describe the combination of this principle with macrocycle formation. PNP-macrocycles were synthesized efficiently in a stereoselective one-pot procedure including the 1,3-dipolar cycloadditions of different dipolarophiles with dimeric cinchona alkaloid-derived azomethine ylides formed in situ. The 20-membered bis-cycloadducts embody 18 stereocenters and an additional fragment-sized NP-structure. After further functionalization, a collection of 163 macrocyclic PNPs was obtained. Biological investigation revealed potent inducers of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy-related processes.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2022. Vol. 61, no 11, article id e202114328
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-192165DOI: 10.1002/anie.202114328ISI: 000746469800001PubMedID: 34978373Scopus ID: 2-s2.0-85123464160OAI: oai:DiVA.org:umu-192165DiVA, id: diva2:1634966
Funder
Swedish Research Council, 2018‐04585Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineAvailable from: 2022-02-04 Created: 2022-02-04 Last updated: 2024-03-27Bibliographically approved
In thesis
1. Non-canonical ATG8 conjugation in ESCRT-driven membrane remodeling processes
Open this publication in new window or tab >>Non-canonical ATG8 conjugation in ESCRT-driven membrane remodeling processes
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Okonventionell ATG8-konjugering i ESCRT-drivna membranombyggnadsprocesser
Abstract [en]

ATG8 family proteins have the unique ability to conjugate to membrane lipids. Initially identified as a hallmark of autophagy, ATG8 lipidation is emerging as an important regulator of a growing list of non-degradative cellular functions. In this thesis we developed and applied novel chemical genetic approaches to perturb dynamic membrane remodeling processes and induce non-canonical ATG8 conjugation in cells. We investigated novel roles of ATG8 in membrane deformation processes carried out by the Endosomal Sorting Complex Requiredfor Transport (ESCRT) machinery.

In Paper I, using a high-throughput phenotypic screening assay, we developed a collection of pseudo-natural product-based compounds which potently induce ATG8 lipidation in mammalian cells. The most potent compound, Tantalosin, induces ATG8 lipidation which is insensitive to simultaneous inhibition of autophagosome-lysosome fusion, suggesting a non-canonical function ofTantalosin-induced ATG8 conjugation.

In Paper II we investigated the molecular target of Tantalosin. We found that Tantalosin targets the ESCRT-III protein IST1 and inhibits IST1-CHMP1B copolymer formation. This inhibition results in the impairment of transferrin receptor (TfR) recycling resulting in the rapid accumulation of the receptor inearly/sorting endosomes. At the same time, Tantalosin induces non-canonical ATG8 conjugation on stalled sorting endosomes containing TfR. This conjugation is dependent on the ATG16L1-ATG5-ATG12 complex which is recruited to stalled endosomes via ATG16L1-V-ATPase interaction.

In Paper III and Paper IV we studied the induction of non-canonical ATG8 lipidation in response to endolysosomal membrane damage. We used two established membrane damaging agents: V. Cholerae cytotoxin MakA and the lysosomotropic compound, LLOMe. In Paper III we demonstrated that, at lowpH, MakA assembles into small pores in endosomal membranes which arerecognized by the ESCRT membrane repair machinery. Non-canonical ATG8 lipidation in response to MakA-induced pore formation is mediated by V-ATPase activity. In Paper IV we identified a novel player in the lysosomal damage response – TECRP1. TECPR1 is recruited to damaged membranes where it forms an alternative ATG16L1-independent E3 ligase complex with the ATG5-ATG12 conjugate and plays a role in the restoration of lysosomal integrity after damage.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 70
Keywords
ATG8 conjugation, Endosomal Sorting Complex Required for Transport, membrane remodeling, chemical genetics
National Category
Cell Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-222756 (URN)978-91-8070-356-7 (ISBN)978-91-8070-357-4 (ISBN)
Public defence
2024-04-26, Stora Hörsalen, KBC byggnad KBE303, 09:00 (English)
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Supervisors
Available from: 2024-04-05 Created: 2024-03-27 Last updated: 2024-03-27Bibliographically approved

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Knyazeva, AnastasiaCorkery, DaleWu, Yao-Wen

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