The disposal of defective or diseased cell components is vital for our cells. Researchers have now discovered that the most important compartments of the cell's own waste disposal system, the lysosomes, have very different structures depending on the cell type. For example, different proteins are found in the lysosomes of liver cells than in kidney or cervical cells. Cancer cells, in turn, have a special variant of lysosomes that are particularly effective at breaking down proteins and can thus supply the growing tumors with important building blocks for their energy metabolism, as the team determined. The knowledge gained about the waste disposal actors in our cells could also help to fathom the cellular roots of certain diseases.
In our cells, there is a constant accumulation of waste materials - defective proteins and cell components, by-products of cell metabolism or even signal molecules that have become superfluous. So that this cellular waste does not accumulate and impair the function of the cell, it is broken down by the cell's own waste disposal system. Central to this disposal are the lysosomes, small sacs in the cytoplasm surrounded by a lipid membrane, in which dozens of different enzymes are collected. Waste material enters these compartments and is then broken down into its individual parts by the various enzymes inside. The result is degradation products in the form of molecules that the cell can use as raw material for further cell processes. "The process is immensely important," explains senior author Dominic Winter from the University Hospital Bonn. "If it doesn't work properly, diseases like Alzheimer's or Parkinson's can result." The lysosomes and their breakdown activity are also immensely important for the energy metabolism of the cell, the defense against pathogens or repair mechanisms.
Comprehensive protein balance of the lysosomes
It has long been known that lysosomes have a very complex structure and can contain several hundred proteins. If you isolate lysosomes from cells and analyze their composition with special equipment, you will often find more than 5000 different proteins. However, it is difficult to determine what function they have in detail and how many of them are essential for the degradation activity of the lysosomes. "It can also be molecules that are being broken down in them," explains Winter. “Others may be attached to their membrane from the outside without performing any task. And also when isolating the lysosomes, there is usually a lot of unwanted bycatch.” Winter, his colleague Fatema Akter and their team have therefore developed a method that can be used to determine the protein content of the lysosomes and identify a large proportion of the uninvolved molecules.
For their study, they applied these analysis methods to six different cell lines, four from humans and two from mice. The human cell cultures came from the kidneys, the cervix, the liver and the bone marrow and some had been taken from cancer tumors. Analysis of the lysosomal proteins revealed that of the 5,000 proteins typically found using conventional methods, a good 1,000 are more closely linked to lysosomal function. A few hundred of these proteins were found in almost all lysosomes - regardless of which tissue they came from. “In addition to the already known lysosomal proteins, there were also about 100 new ones. We consider it likely that these also play an important role in the functioning of the nano-shredders,” explains Winter.
Different equipment depending on the cell type
In addition, however, there are many proteins that appear to be found only in the lysosomes of certain tissues. Other proteins, on the other hand, differ in their proportion and quantity depending on the cell type. "In each of the six cell types that we examined, the lysosomes have a very specific protein configuration," reports Winter. "As far as I know, we are the first working group that was able to show this." The disposal factories of the cells are therefore specifically structured depending on the tissue and cell type and each have their own set of protein tools adapted to the needs of the cells. "The lysosomes of liver cells, for example, are full to the brim with degradation enzymes," reports Winter. "That is also plausible - an important function of the liver is the breakdown of different molecules." The liver plays an important role in detoxifying the body.
Cancer cells, on the other hand, have a special variant of lysosomes that can supply them with building blocks for their energy metabolism in a particularly effective manner. "In the cancer cells we examined, the lysosomes contained a large number of transporter proteins," reports Winter. The reason for this: tumors need a lot of energy to grow, and at the same time they often have poor blood circulation. They therefore digest the surrounding tissue with the help of the lysosomes and use the breakdown products to generate energy. So that these can then be used by the cancer cell, they have to be transported back into the cell from the lysosomes - hence the many transporter proteins.
Overall, the results help elucidate more about the function and workings of the lysosome. But they could also help elucidate the role of lysosomes in certain diseases. It has been known for a long time that the lysosomes in certain nerve cells are altered in Parkinson's disease. "We can now take a kind of protein fingerprint of these lysosomes and compare them with those of healthy people," explains Winter. "That could provide clues as to how the function of the cellular shredders is changed in those affected and why this leads to neurological problems." In the long term, this could also help to find new starting points for drugs.
Source: Fatema Akter (University of Bonn) et al., Molecular & Cellular Proteomics, doi: 10.1016/j.mcpro.2023.100509