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A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.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). Science for Life Laboratory, Umeå University, Umeå, Sweden.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.ORCID iD: 0000-0001-7930-0134
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). 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, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0002-0011-3756
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2024 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 121, no 17, article id e2317680121Article in journal (Refereed) Published
Abstract [en]

The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging. This study presents a pseudonatural product targeting IST1-CHMP1B within the ESCRT-III complexes. The compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting, or biogenesis of extracellular vesicles, it rapidly inhibits transferrin receptor recycling in cells, resulting in the accumulation of transferrin in stalled sorting endosomes. Stalled endosomes become decorated by lipidated LC3, suggesting a link between noncanonical LC3 lipidation and inhibition of the IST1-CHMP1B complex.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences , 2024. Vol. 121, no 17, article id e2317680121
Keywords [en]
endosomal recycling, ESCRT, IST1-CHMP1B, noncanonical LC3 lipidation, Tantalosin
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-225949DOI: 10.1073/pnas.2317680121ISI: 001222975200010PubMedID: 38635626Scopus ID: 2-s2.0-85191105662OAI: oai:DiVA.org:umu-225949DiVA, id: diva2:1868749
Funder
EU, European Research CouncilSwedish Research Council, 2018-04585Swedish Research Council, 2022-02932Swedish Research Council, 2018–05851Swedish Research Council, 2021–01145Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineAvailable from: 2024-06-12 Created: 2024-06-12 Last updated: 2024-06-12Bibliographically approved

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Knyazeva, AnastasiaLi, ShuangCorkery, Dale P.Shankar, KasturikaHerzog, Laura K.Singh, BirendraGilthorpe, Jonathan D.Carlson, Lars-AndersWu, Yao-Wen

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Knyazeva, AnastasiaLi, ShuangCorkery, Dale P.Shankar, KasturikaHerzog, Laura K.Singh, BirendraGilthorpe, Jonathan D.Carlson, Lars-AndersWu, Yao-Wen
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Wallenberg Centre for Molecular Medicine at Umeå University (WCMM)Molecular Infection Medicine Sweden (MIMS)Department of Medical Biochemistry and BiophysicsAnaesthesiologyDepartment of Integrative Medical Biology (IMB)
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Proceedings of the National Academy of Sciences of the United States of America
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