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Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomes
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). (Yaowen Wu)ORCID iD: 0000-0001-8504-9126
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
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0002-0011-3756
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0002-3322-7864
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(English)Manuscript (preprint) (Other academic)
National Category
Cell Biology Biochemistry and Molecular Biology
Research subject
cell research; biological chemistry; biology
Identifiers
URN: urn:nbn:se:umu:diva-222750DOI: 10.1101/2023.08.28.555152OAI: oai:DiVA.org:umu-222750DiVA, id: diva2:1847281
Available from: 2024-03-27 Created: 2024-03-27 Last updated: 2024-03-27
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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Available from: 2024-04-05 Created: 2024-03-27 Last updated: 2024-03-27Bibliographically approved

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Knyazeva, AnastasiaCorkery, DaleShankar, KasturikaHerzog, Laura K.Singh, BirendraGilthorpe, Jonathan D.Carlson, Lars-AndersWu, Yao-Wen

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Knyazeva, AnastasiaCorkery, DaleShankar, KasturikaHerzog, Laura K.Singh, BirendraGilthorpe, Jonathan D.Carlson, Lars-AndersWu, Yao-Wen
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Department of Medical Biochemistry and BiophysicsWallenberg Centre for Molecular Medicine at Umeå University (WCMM)Molecular Infection Medicine Sweden (MIMS)AnaesthesiologyDepartment of Integrative Medical Biology (IMB)
Cell BiologyBiochemistry and Molecular Biology

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