How cells self-clean to survive stress and disease

Cleaning and decluttering our homes can often be put off, but living cells cannot afford such procrastination when it comes to clearing out waste. Within cells, tiny garbage chutes called autophagosomes are constantly active, capturing worn-out proteins, faulty components, and defective organelles. These autophagosomes prevent the accumulation of waste that could damage the cell. The cellular waste is then delivered to the lysosome, the cell’s recycling machinery, where it is digested and recycled.

This process of autophagy, or self-eating, provides cells with quick access to building blocks for new components and helps them survive stress or periods of starvation. Autophagy also plays a crucial role in neutralizing viruses and bacteria that manage to bypass the immune system and enter the cell plasma. If autophagy is faulty, too slow, or too fast, it can have severe consequences. Neurodegenerative diseases, cancer, immune system disorders, and accelerated aging processes can occur.

The process of autophagy is highly complex and involves numerous proteins and protein complexes. Although many components are known, there are still significant gaps in our understanding. Research groups, such as the one led by Alex Faesen at the Max Planck Institute for Multidisciplinary Sciences in Göttingen, are actively working to unravel the intricacies of autophagy. Their aim is to uncover how the protein components work together, how the autophagy process is initiated and halted, and when and where the autophagosome assembly takes place.

Nanomachine at work

After years of collaborative effort with teams led by Björn Stork from the University of Düsseldorf and Michael Meinecke, formerly at the University Medical Center Göttingen and now at Heidelberg University Biochemistry Center, Alex Faesen’s research group has achieved a significant breakthrough. They have successfully produced all the proteins involved in the autophagy process in the laboratory and directly observed the assembly of autophagosomes. The findings of their study have been published in the journal Molecular Cell.

The research team encountered numerous challenges throughout the process. Initially, they attempted to produce the individual protein components using genetically reprogrammed bacteria, a common approach for large-scale protein production. However, this method failed for all their proteins. Eventually, they switched to using insect cells, which proved to be a pivotal breakthrough.

Once they had successfully produced the individual protein components, the team proceeded to bring them together to form protein complexes. These complexes then self-assembled into a supercomplex known as the autophagy initiation complex. This discovery revealed that the cellular nanomachine involved in autophagy is more sophisticated and operates differently than previously believed.

To generate autophagosomes, the autophagy initiation complex creates a connection between a specific cellular structure called the endoplasmic reticulum and the forming autophagosome. This process occurs rapidly, within a matter of minutes, under conditions of stress or during periods of starvation. Once the connection is established, the autophagy machinery begins collecting cellular waste, enclosing it within the growing autophagosome. Within approximately 20 minutes of its formation, the autophagosome fuses with the lysosome, delivering its cargo for degradation.

The study’s co-first authors, Anh Nguyen and Francesca Lugarini, emphasize the crucial role of a contact site where lipids, resembling fat-like molecules, are transported to a precursor stage of autophagosomes and incorporated into their structure. As the autophagosomes grow, they encapsulate the cellular material destined for disposal, ultimately forming fully functional mini-organelles.

These groundbreaking findings shed new light on the intricacies of the autophagy process, providing a deeper understanding of its underlying mechanisms.

Protein origami for ‘on’ and ‘off’

In the quest to understand the initiation and regulation of the autophagy process, the researchers made an intriguing discovery: there is no conventional molecular “on” and “off” switch as found in other molecular machines. Instead, they observed a remarkable behavior in certain proteins, specifically ATG13 and ATG101. These proteins have the ability to undergo metamorphosis, meaning they can adopt different 3D structures. This metamorphosis directly influences their ability to bind to other proteins within the autophagy machinery.

The ability of ATG13 and ATG101 to transition between different structural conformations serves as the crucial switch for initiating the assembly of the autophagy initiation complex at the precise time and location. Alex Faesen highlights the significance of this protein metamorphosis, describing it as a unique characteristic of the nanomachine. Without this metamorphosis, the assembly of the initiation complex does not occur.

These findings open up exciting possibilities for the development of future drugs that could target and modulate the autophagy process. By understanding the mechanisms of autophagy initiation and regulation, researchers hope to pave the way for novel therapeutic interventions to treat diseases associated with dysregulated autophagy.

The newfound insights into the autophagy process, particularly the role of protein metamorphosis, hold promise for advancing our understanding of autophagy-related disorders and potentially devising strategies to restore proper autophagy function in these conditions.

Source: Max Planck Society

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