Recycling occurs continuously in our cells: a mechanism known as autophagy sees that cell components that are no longer necessary are encapsulated by membranes and dismantled into their fundamental building blocks. This essential process prevents the development of detrimental aggregates and makes nutrients available again.
A research group co-directed by Prof. Dr. Claudine Kraft from the CIBSS Cluster of Excellence at the University of Freiburg and Dr. Florian Wilfling from the Max Planck Institute of Biophysics in Frankfurt has now identified the required conditions for autophagy to initiate. They successfully managed to artificially produce these conditions, thus prompting the breakdown of otherwise indestructible molecules in yeast cells. Targeting autophagy in this manner represents a promising strategy to encourage the degradation of aggregates that might otherwise lead to plaques in neurodegenerative diseases like Alzheimer’s, as well as to enhance the effectiveness of cancer therapies. The research has been published in the scientific journal Nature Cell Biology.
Weak molecular associations crucial for autophagy initiation
For cellular degradation via autophagy to happen, the components must first be identified as waste. This recognition is performed by receptor and various adapter molecules. However, it was previously unclear how precisely these molecules activated the subsequent stages. “We have now demonstrated that the receptors must engage weakly with the materials designated for disposal for autophagy to commence,” explains Kraft. “If they bind too firmly, the process does not initiate.”
This initially perplexing finding can be clarified by the researchers through computer simulations and studies on living yeast cells and human cells in culture: the weak binding allows the receptors to stay dynamic and form random clusters. “When the critical concentration threshold is reached, phase separation occurs: the adapter molecules coalesce and create a droplet, akin to oil in water,” elucidates Wilfling. “Such a liquid accumulation exhibits different physical characteristics compared to the individual molecules, creating a flexible platform for all other substances involved in autophagy.”
The process can be manipulated artificially
To test their theory, the researchers introduced virus particles into yeast cells that the cells typically cannot degrade. By adjusting the virus particles so that autophagy receptors could weakly attach to them, the researchers managed to induce the breakdown of the viral protein. However, if they altered the surface so that the receptors bound strongly, no degradation occurred. “This outcome is encouraging since it suggests that we are able to specifically interfere in the autophagy of cellular cargo,” conclude both Kraft and Wilfling.
The research was supported by the German Research Foundation (EXC-2189; SFB 1381; SFB 1177; 450216812; 409673687; GRK 2606;) the European Research Council under the Horizon 2020 program (ERC 769065), the Max Planck Society, and the European Union (ERC 101041982).
-Note: This news release was initially published by the University of Freiburg. As it has been republished, it may differ from our style guide.