New insights into the cell’s cleaning system

2020

Challenge

A process called autophagy is the body’s way of getting rid of damaged and diseased cells and harmful proteins. Autophagy relies on structures called autophagosomes that engulf and destroy unwanted cellular materials, but how autophagosomes are created in the first place remains poorly understood. A protein called ATG9 is thought to play a key role in the construction of autophagosomes because it is the only protein that crosses the autophagosome’s two membranes, but no high-resolution image of its three-dimensional structure has ever been published.

Advance

A team of IRP researchers led by Anirban Banerjee, Ph.D., used computer simulations to generate a three-dimensional structural image of the ATG9 protein, which allowed the team to show how the shape of the protein determines its function. The team found that three ATG9 molecules join together to form a wedge that pokes through the autophagosome membrane. Intriguingly, a network of connected cavities run through the protein across the membrane, suggesting that the function of ATG9 is to move fat molecules called lipids, which make up the autophagosome’s membrane, from one side of the membrane to the other.

Impact

These results offer a possible answer to the longstanding question of how lipids are distributed over either side of the autophagosome’s membrane as it grows. In this way, the research addresses a key missing piece in our understanding of how autophagosomes work. Moreover, the scientists’ high-resolution structure of ATG9 will guide many future experiments examining how the protein interacts with other components of autophagosomes, how malfunctions in ATG9 can contribute to disease, and what therapeutic targets could help alleviate illnesses related to malfunctioning autophagy, such as neurodegenerative diseases, various forms of cancer, and heart disease.

Publications

Guardia CM, Tan XF, Lian T, Rana MS, Zhou W, Christenson ET, Lowry AJ, Faraldo-Gómez JD, Bonifacino JS, Jiang J, Banerjee A. (2020). Structure of human ATG9A, the only transmembrane protein of the core autophagy machinery. Cell Rep. 2020 Jun 30;31(13):107837. doi: 10.1016/j.celrep.2020.107837.