期刊
NATURE CHEMICAL BIOLOGY
卷 15, 期 7, 页码 710-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-019-0307-5
关键词
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资金
- Max Planck Society
- DFG [SPP 1623]
- ERC (ChemBioAP)
- Vetenskapsradet [2018-04585]
- Knut and Alice Wallenberg Foundation
- Alexander von Humboldt Stiftung
- Canadian Institute of Health Research [MFE-152550]
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.
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