Recycling takes place in our cells all the time: in a process called autophagy, cellular components that are no longer needed are enclosed by membranes and broken down into their basic components. This vital process prevents the formation of harmful aggregates and makes nutrients available again.
A research team co-led by Prof. Dr. Claudine Kraft from the CIBSS Group of Excellence at the University of Freiburg and Dr. Florian Wilfling from the Max Planck Institute for Biophysics in Frankfurt has discovered the conditions necessary for autophagy to begin. They were also able to artificially create these conditions and thus trigger the degradation of otherwise non-degradable molecules in the yeast cells. Targeting autophagy in this way is a promising approach to promote the degradation of aggregates that might otherwise form plaques in neurodegenerative diseases such as Alzheimer’s, as well as to improve the efficacy of anti-cancer treatments. The study has been published in the scientific journal. nature cell biology.
Weak molecular interactions essential for autophagy to begin
For degradation of cellular components through autophagy to occur, they must first be recognized as waste. This is done by the receptor and other adapter molecules. However, until now it was unknown how exactly these molecules trigger the following steps. “We have now been able to show that for autophagy to begin, the receptors must bind weakly to the material to be eliminated,” explains Kraft. “If they join together too tightly, the process does not trigger.”
What initially seems contradictory, the researchers were able to explain with the help of computer simulations and experiments with living yeast cells and human cells in cell cultures: the weak binding causes the receptors to remain mobile and form random clusters. “When the critical concentration point is reached, a phase separation occurs: the adapter molecules come together and form a drop, similar to oil in water,” explains Wilfling. “This accumulation of fluid has different physical properties than individual molecules and serves as a flexible platform for all other molecules involved in autophagy.”
The process can be controlled artificially.
To test their hypothesis, the researchers introduced virus particles into yeast cells that they normally cannot break down. By modifying the virus particles so that autophagy receptors could weakly bind to them, the researchers were able to trigger degradation of the viral protein. However, if they modified the surface so that the receptors bound strongly to it, no degradation occurred. “This result is promising because it shows that we can specifically intervene in the autophagy of cargo molecules in living cells,” summarize Kraft and Wilfling.
The study was funded by the German Research Foundation (EXC-2189; SFB 1381; SFB 1177; 450216812; 409673687; GRK 2606;) by the European Research Council within the framework of the Horizon 2020 program (ERC 769065), the Max Society Planck and for the European Union (ERC 101041982).