2. Academic Validation
  3. The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis

The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis

  • Nat Chem Biol. 2019 Jul;15(7):710-720. doi: 10.1038/s41589-019-0307-5.
Luca Laraia 1 2,  Alexandra Friese 1,  Dale P Corkery 3 4,  Georgios Konstantinidis 3 4,  Nelli Erwin 5,  Walter Hofer 1,  Hacer Karatas 1,  Laura Klewer 3,  Andreas Brockmeyer 1,  Malte Metz 1,  Beate Schölermann 1,  Mridula Dwivedi 5,  Lei Li 5,  Pablo Rios-Munoz 6 7,  Maja Köhn 6 7,  Roland Winter 5,  Ingrid R Vetter 1,  Slava Ziegler 1,  Petra Janning 1,  Yao-Wen Wu 8 9,  Herbert Waldmann 10 11
Affiliations

Affiliations

  • 1 Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
  • 2 Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
  • 3 Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.
  • 4 Department of Chemistry, Umeå University, Umeå, Sweden.
  • 5 Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
  • 6 Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
  • 7 Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 8 Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany. yaowen.wu@umu.se.
  • 9 Department of Chemistry, Umeå University, Umeå, Sweden. yaowen.wu@umu.se.
  • 10 Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany. herbert.waldmann@mpi-dortmund.mpg.de.
  • 11 Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany. herbert.waldmann@mpi-dortmund.mpg.de.
PMID: 31222192 DOI: 10.1038/s41589-019-0307-5
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.

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