Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
Nat Chem Biol. 2019 Jul;15(7):710-720. doi: 10.1038/s41589-019-0307-5. Epub 2019 Jun 20.
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.
自噬介导受损蛋白质、细胞器和病原体的降解，在健康和疾病中发挥着关键作用。因此，鉴定新的自噬调控机制具有重要意义。特别是，关于脂质和脂质结合蛋白在自噬体生物发生的早期步骤中的作用知之甚少。我们使用靶向非特异性、高内涵、基于图像的方法鉴定小分子诱导的指示表型变化，发现自噬素是一类新的自噬抑制剂。自噬素选择性地靶向最近发现的胆固醇转移蛋白 GRAM 结构域包含蛋白 1A（GRAMD1A，其以前与自噬无关），并直接与胆固醇竞争与 GRAMD1A StART 结构域结合。GRAMD1A 在自噬体起始部位积累，影响饥饿时胆固醇的分布，并且是自噬体生物发生所必需的。这些发现确定了 GRAMD1A 的新生物学功能以及胆固醇在自噬中的新作用。
