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16 January 2025

Decoding the mechanism behind autophagy

Researchers combined advanced imaging techniques to uncover how cells recognize and degrade unwanted components, offering new insights into the autophagy process

New research led by Prof. 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 unveiled critical insights into the process of autophagy – the cell's natural recycling system. Published in Nature Cell Biology, the study provides a new understanding of how our cells recognize and degrade unwanted components, a process essential for maintaining health and preventing disease.

Autophagy, which literally means "self-eating," is a continuous process in which cellular components that are no longer needed are enclosed by membranes and broken down into their basic building blocks. This mechanism plays a crucial role in preventing the formation of harmful aggregates that can lead to neurodegenerative diseases, such as Alzheimer's, and in regulating cellular health. However, until now, the precise conditions necessary to trigger autophagy have remained unclear.

 

Under the fluorescence microscope: the Atg11 molecule (green) forms small droplets on the surface of a protein aggregate (blue). (Image Credit: Mariya Licheva / University of Freiburg)

 

Weak molecular interactions trigger autophagy

The research team discovered that autophagy is initiated when receptors responsible for recognizing cellular waste bind weakly to the material that needs to be discarded. "If they bind too strongly, the process is not triggered," explains Prof. Kraft. This discovery was made possible through a combination of advanced imaging techniques, including fluorescence, time-lapse, and cryo-scanning electron microscopy.

Using fluorescence microscopy, the researchers were able to track the dynamic behavior of receptors in living cells. This imaging technique allowed them to visualize how the receptors bind to cargo and undergo the crucial step of clustering. Live cell imaging and time-lapse microscopy further revealed how the receptor molecules remained mobile and spontaneously formed random clusters, providing key insights into the early stages of autophagy. In addition, cryo-scanning electron microscopy provided high-resolution images of the cellular structure, allowing the researchers to observe the physical changes in the cells that occur during autophagy.

The key finding? Weak binding allows the receptors to remain mobile and cluster randomly, eventually reaching a "critical concentration" that causes the molecules to separate and form liquid droplets, much like oil in water. These droplets serve as flexible platforms, bringing together all the necessary components to begin the degradation process.

Artificially triggering degradation

In a remarkable breakthrough, the researchers demonstrated the ability to artificially trigger autophagy in yeast cells. By modifying virus particles in a way that allowed weak binding with autophagy receptors, the team was able to induce the degradation of the viral protein. On the other hand, when the receptors were encouraged to bind more strongly, no degradation occurred.

"This result is promising because it shows that we can specifically intervene in the autophagy of cargo molecules of living cells," said Kraft and Wilfling, who believe their findings open new possibilities for therapeutic strategies. By targeting autophagy in this way, it may be possible to promote the breakdown of harmful aggregates in diseases like Alzheimer's or improve the effectiveness of cancer treatments.

Original Publication:

Licheva, M. et al.: Phase separation of initiation hubs on cargo is a trigger switch for selective autophagy. Nat Cell Biol (2025); DOI: 10.1038/s41556-024-01572-y

About the authors

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    Inara Aguiar

    Inara is a science communicator with a Ph.D. in Inorganic Chemistry. After a postdoc in Computational Chemistry, she became a science editor specializing in Chemistry, Engineering, Bioengineering, and Biochemistry. With several years of experience in scientific writing and editing, she collaborates with Wiley Analytical Science, covering topics like microscopy and spectroscopy.

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