The double life of cellular "glue": scientists have uncovered a new protein function

The protein E-cadherin, which helps cells connect to each other, turned out to be a participant in another important process — the removal of dead cells. The researchers found that the epithelium can absorb them while maintaining the integrity of the protective layer of tissue. How this system works, why cell flexibility is important for it, and what the discovery can do to study inflammation is described in the Izvestia article.

Why should tissues remove dead cells?

Cell death by itself does not necessarily mean disease. One of its variants is apoptosis, or programmed cell death. It is a sequence of molecular events by which the body gets rid of unnecessary or abnormal cells.

However, ending the life of a cell and removing it from the tissue are different tasks. The dead material must be removed in a timely manner. If this does not happen, the cells can break down and release their contents, contributing to inflammation.

The absorption and removal of cellular residues is usually associated with the work of phagocytes, in particular, specialized cells of the immune system. But epithelial cells are also capable of participating in such purification. They form the surface layers of tissues, including covering the skin and lining the intestines and respiratory tract.

For them, there is an additional difficulty. The epithelial cell remains part of the overall protective layer: it needs to capture a dead neighbor and at the same time maintain connections with the surrounding tissue. The group led by Verena Ruprecht studied exactly how she combines these actions.

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What does cellular "glue" do?

The work focused on the E-cadherin complex, a system consisting of the protein itself and its three partners. In normal intercellular contacts, E-cadherin on the surface of one cell interacts with the same protein on the neighboring one. Together with other components of the complex, it helps maintain cell cohesion and mechanical stability of the tissue.

Therefore, in the popular description it is called cellular "glue". However, this comparison conveys only part of the work of the molecular system. Observations of living embryos have shown that the complex also gathers where the epithelial cell comes into contact with the dead cell to be absorbed.

Thus, the same molecular components are involved in two different actions: they maintain connections between living cells and help tissue remove dead material.

How scientists tested a new protein function

First, the researchers looked at the most obvious explanation. Perhaps the epithelium captures the dead cell using the same E-cadherin interaction that connects living neighbors. In this case, the protein would have to be present on both sides of the contact.

To test this hypothesis, the tissues were offered dying cells devoid of E-cadherin. Their removal was as effective as in the case of ordinary dying cells. This means that the presence of this protein on the most absorbed cell was not a prerequisite.

The scientists then used artificial lipid objects that did not contain proteins. A signal characteristic of dying cells was present on their surface. Epithelial cells also absorbed such objects.

These experiments helped to separate the new function of the complex from the usual coupling of two cells. However, they do not mean that E-cadherin recognizes the death signal itself. The study shows its involvement in the mechanical organization of absorption — the ability of a cell to change shape and make the necessary efforts.

How does a cell change shape without breaking the barrier

To absorb a large object, the cell must extend sections of its surface, grasp it and gradually enclose it inside. For a single mobile cell, this is one mechanical task. For a cell embedded in a dense epithelial layer, it is different: significant shape changes should not disrupt the integrity of the tissue.

Taking pictures of live embryos allowed us to see how this problem is being solved. Opposite sides of the same epithelial cell behave differently. Its lower, or basal, surface actively deforms and covers the dead cell. The upper, or apical, side remains relatively stable.

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Depending on the tissue, the apical surface may face the external environment or the lumen of the organ. It is on this side that it is important to maintain the continuity of the protective layer. Measurements before, during and after absorption showed that the area of the upper surface changed slightly, while the lower one was noticeably rearranged.

Ruprecht compared this process to a series of dancers holding hands. Their upper body remains stable, while their legs perform increasingly complex movements. So the cell can actively work with one side, maintaining the position and connections of the other.

This observation explains why the absorption of dead material does not require a complete change in the shape of the cell or its exit from the common layer. Different parts of its surface are capable of performing different mechanical tasks simultaneously.

Why does the takeover need a "cable" and a "brake"

The researchers also found out which components of the complex allow the cell to do this job. Alpha-catenin turned out to be one of the key participants. It binds the molecular complex to the actin cytoskeleton, an internal system of protein filaments involved in cell movement and shape change.

In the authors' figurative description, alpha-catenin works like a "cable": it transmits the force necessary to grasp the absorbed object. When the cell was deprived of this protein or its actin binding site, absorption was disrupted.

Another component, p120-catenin, acts as a "brake". It limits the activity of myosin II, a protein involved in cell contraction. It turned out that in order to successfully remove dead cells, it is important not only to create an effort, but also to keep it within suitable limits.

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Without such control, the lower surface of the cage became excessively stressed, and cleaning deteriorated. Moreover, the authors showed that a decrease in the activity of myosin II could restore the absorption disrupted by the intervention of p120-catenin.

This is one of the most significant results of the work. A stronger contraction does not necessarily help the cell to cope with the task. To wrap itself around a large object, it needs both the transfer of effort and the ability to freely change shape.

Why were the experiments conducted on embryos?

Scientists conducted the main observations on zebrafish embryos. These models allow detailed monitoring of the behavior of living cells and tissues using microscopy. The researchers could see not only the outcome of the absorption, but also the sequence of movements that leads to it.

The team then tested the involvement of E-cadherin in early mouse embryos. When his work was blocked, the dying cells remained undeleted. The result is consistent with observations in fish and indicates the similarity of the mechanism in the two groups of vertebrates.

The work continues earlier research by Ruprecht's team on the joint removal of dying cells by the embryo's epithelium. Such activity is a form of early innate defense.

However, the presence of a similar process in fish and mice does not yet answer the question of its work in the adult body. The conditions in the developing embryo are different from those in the mature tissue. Therefore, the next step is to find out where else this particular system with the participation of E-cadherin is used.

What can this discovery provide for the study of inflammation?

Adult epithelial cells already have the ability to remove dead material, for example, in the retina, colon, respiratory tract, and mammary gland. E-cadherin is also widely present in the epithelium, and its structure has changed little over the course of evolution. This gives grounds to check whether the described mechanism is involved in the purification of such tissues.

So far, scientists have not established whether it works in adult fish and mice or in any human tissues. The study also did not test the treatment of inflammatory diseases. Its significance at this stage lies in explaining how one of the processes of removing dead cells works.

This is an essential question for studying inflammation. If cellular residues are trapped in the tissue and destroyed, their contents can support an inflammatory response. To understand the causes of the malfunction, it is necessary to examine not only the recognition signals of the dead cell, but also the physical ability to absorb it.