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Proteins protect cells from stressful forces and diseases such as muscular dystrophy by forming “nanoclusters”
A team of USC Dornsife scientists uncovers new evidence of how the protein emerin works and its link to rare and debilitating Emery-Dreifuss muscular dystrophy.
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Scientists have revealed how a protein called emerin works to enable cells to adapt to stressful physical forces. The work provides new understanding of the protein’s role in diseases such as Emery-Dreifuss muscular dystrophy (EDMD).
The news: Scientists at USC Dornsife College of Letters, Arts and Sciences have discovered that emerine responds to harmful mechanical forces exerted on the cell by clustering together to form so-called “nanoclusters.”
Emerin nanoclusters help stabilize and protect the nuclear envelope, the membrane surrounding the nucleus, from damage and rupture.
The nucleus houses the cell’s genetic material and the machinery that translates the genetic code from DNA into proteins.
Emerin combines with other nuclear membrane proteins to help maintain the shape and integrity of the membrane.
In their words:
“The rearrangement of emerine into nanoclusters is crucial to properly adapt the nucleus to mechanical stress. In fact, cells without emerine or with defective emerine assemblies could not respond properly to mechanical stresses. — Fabien Pinaud, associate professor of biological and physical sciences and astronomy at USC Dornsife and corresponding author.
Also important: Emerin is a key molecular player in the ability of cells to cope with mechanical stress and must function normally for cells to respond properly to these forces.
The researchers found that mutant forms of emerine known to cause EDMD were unable to properly self-assemble, rendering the cell nucleus “impotent in its response to mechanical challenges.”
These results provide further evidence and understanding of the role of emerine in EDMD.
Emery-Dreifuss muscular dystrophy is a rare genetic disease affecting the muscles.
Symptoms usually begin to appear around age 10 and gradually worsen over time.
Early symptoms include weakness and degeneration of muscles in the legs, arms and shoulders as well as stiff joints. Later, the heart is often affected as well as the muscles involved in breathing.
Patients frequently become dependent on a wheelchair and other aids, and usually die in mid-adulthood.
In the lab: To test the role of emerine, Anthony Fernandez and other graduate students at the Pinaud lab induced mechanical stresses on cells by forcing them into unusual rectangular shapes, then used highly advanced microscopy techniques to see how Emery reacted.
The researchers were able to image emerine in cells at resolutions never before achieved.
The ultra-high-resolution images revealed how emerine rearranges itself on a molecular scale of just a few nanometers, Pinaud said.
In their words:
“Silhouette shaping of cells and the use of highly advanced microscopy techniques have been instrumental in showing that emerine reorganization at the scale of nanometers is essential for cellular adaptation and for surviving changes in mechanical conditions, such as would be found when muscles are working,” Pinaud said.
Pinaud says the research provides deeper insight into the importance of the nucleus in the response to mechanical stress on cells.
“The average person usually thinks the nucleus just houses our genetic material,” he said. “Our findings show how important the nucleus is to the mechanical response of the cell, and that the nucleus itself must be able to adapt to mechanical challenges to prevent cell injury and death.”
More: Pinaud says the study also demonstrates the important role advanced imaging plays in revealing how cellular processes work and can lead to disease.
“Most importantly, we have shown that these crucial reorganizations take place over only a few tens of nanometers, a length scale that remains inaccessible by conventional optical microscopy imaging,” he said. “Our results underscore the importance of peering into biological processes at the highest possible optical resolution and looking into intact cells to better understand fundamental systems of cell biology and disease development.”
Next: Pinaud says the team wants to learn more about the forces that act on the nuclear membrane and the role of other proteins in helping cells respond to mechanical forces.
The team is developing methods that use light to directly measure the forces exerted on the nuclear membrane. These forces are on the order of a few tens of piconewtons, or about 1 billion times less than the force required to prevent a dollar bill from falling to the ground.
They also want to explore emerine’s interaction with the LINC complex – a group of cellular proteins that play multiple vital roles, including sensing forces on the cell.
About the study
The authors of the study, which appears in the Journal of Cell Science, include Pinaud, Fernandez and doctoral students Markville Bautista and Liying Wu, all of USC Dornsife.
The research was supported by grant number R21AR076514 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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From left, cells (green) and their nuclei (blue) at rest and under increasing mechanical stress on rectangular micropatterns with widths of 15, 10 and 5 micrometers.
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Reproduced and adapted with permission from the Journal of Cell Science.