Recycling takes place in our cells at all times: in a process called autophagy, cell components that are no longer needed are enclosed by membranes and broken down into their basic building blocks. 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 Cluster of Excellence at the University of Freiburg and Dr. Florian Wilfling from the Max Planck Institute of Biophysics in Frankfurt has now discovered the conditions necessary for autophagy to start. They were also able to artificially create these conditions and thus trigger the degradation of otherwise non-degradable molecules in yeast cells. Targeting autophagy in this way is a promising approach for promoting the degradation of aggregates that can otherwise form plaques in neurodegenerative diseases such as Alzheimer's, as well as to improve the efficacy of cancer treatments. The study has been published in the scientific journal Nature Cell Biology.

Weak molecular interactions play a crucial role in initiating the process of autophagy.

For the process of autophagy to effectively degrade cellular components, these components must first be identified as waste. This identification is facilitated by receptor and various adapter molecules. Until now, the precise mechanism by which these molecules initiate the subsequent actions was unclear. "Our research has revealed that the receptors need to establish a weak binding with the waste material in order for autophagy to commence," states Kraft. "If the binding is too strong, the process fails to initiate."

What may seem paradoxical at first can be clarified by researchers utilizing computer simulations and experiments involving living yeast cells and human cell cultures: the low affinity of the binding allows the receptors to stay mobile and create random clusters.

Once the critical concentration threshold is achieved, phase separation takes place: the adapter molecules aggregate to create a droplet, akin to oil dispersed in water. This liquid formation exhibits distinct physical characteristics compared to the individual molecules, functioning as a dynamic platform for other molecules participating in the autophagy process.

Dr. Florian Wilfling from the Max Planck Institute for Biophysics located in Frankfurt.

The process can be regulated through artificial means.

In order to validate their hypothesis, the researchers inserted virus particles into yeast cells, which typically cannot degrade these particles. They altered the virus particles to allow weak binding with autophagy receptors, successfully initiating the breakdown of the viral protein. Conversely, when they enhanced the surface modifications to enable strong binding of the receptors, degradation did not occur. "This finding is encouraging as it demonstrates our ability to selectively influence the autophagy process of cargo molecules within living cells," both Kraft and Wilfling summarized.