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The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis
Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.ORCID iD: 0000-0001-7930-0134
Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.
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2019 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 15, no 7, p. 710-720Article in journal (Refereed) Published
Abstract [en]

Autophagy mediates the degradation of damaged proteins, organelles and pathogens, and plays a key role in health and disease. Thus, the identification of new mechanisms involved in the regulation of autophagy is of major interest. In particular, little is known about the role of lipids and lipid-binding proteins in the early steps of autophagosome biogenesis. Using target-agnostic, high-content, image-based identification of indicative phenotypic changes induced by small molecules, we have identified autogramins as a new class of autophagy inhibitor. Autogramins selectively target the recently discovered cholesterol transfer protein GRAM domain-containing protein 1A (GRAMD1A, which had not previously been implicated in autophagy), and directly compete with cholesterol binding to the GRAMD1A StART domain. GRAMD1A accumulates at sites of autophagosome initiation, affects cholesterol distribution in response to starvation and is required for autophagosome biogenesis. These findings identify a new biological function of GRAMD1A and a new role for cholesterol in autophagy.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 15, no 7, p. 710-720
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:umu:diva-161576DOI: 10.1038/s41589-019-0307-5ISI: 000472625600015PubMedID: 31222192OAI: oai:DiVA.org:umu-161576DiVA, id: diva2:1338953
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Max Planck SocietySwedish Research Council, 2018-04585Knut and Alice Wallenberg FoundationAvailable from: 2019-07-25 Created: 2019-07-25 Last updated: 2019-07-25Bibliographically approved

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Corkery, DaleWu, Yao-Wen

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