The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis

Luca Laraia, Alexandra Friese, Dale P. Corkery, Georgios Konstantinidis, Nelli Erwin, Walter Hofer, Hacer Karatas, Laura Klewer, Andreas Brockmeyer, Malte Metz, Beate Schölermann, Mridula Dwivedi, Lei Li, Pablo Rios-Munoz, Maja Köhn, Roland Winter, Ingrid R. Vetter, Slava Ziegler, Petra Janning, Yao Wen WuHerbert Waldmann*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
JournalNature Chemical Biology
Volume15
Issue number7
Pages (from-to)710-720
Number of pages11
ISSN1552-4450
DOIs
Publication statusPublished - 2019

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