Scientists have uncovered a novel mechanism through which skin cells organize and control protein production during homeostasis and wound healing, according to a new study published in Developmental Cell.
The findings offer new details on how skin tissues maintain their protective barriers and how they respond when those barriers are breached, said Rui Yi, PhD, the Paul E. Steiner Research Professor of Pathology and professor of Dermatology, who was a co-author of the study.
For decades, scientists have known that cells divide their internal space into compartments, helping to coordinate the thousands of chemical reactions that keep them alive. The new study shows that this organizational principle extends to protein synthesis itself, Yi said.
“Traditionally, scientists assumed that in epithelial cells, mRNAs are more or less evenly distributed in the cytosol,” Yi said. “The idea was that proteins are made anywhere in the epithelial cell, and then the proteins go where they need to function. What we found challenges that dogma.”
In the study, investigators analyzed mouse and human epidermal cells and discovered that some of the molecular machinery responsible for making proteins — ribosomes — are recruited by desmosomes, the molecular structures responsible for fastening neighboring cells together, and are localized near the outer membrane, or cortex, of the cell rather than evenly distributed throughout the interior.
Along with ribosomes, a large group of messenger RNAs (mRNAs) — the genetic instructions that ribosomes read to build proteins — also cluster at the cellular perimeter. Together, these findings define a previously unrecognized system of mRNA organization, suggesting that where an mRNA sits inside a cell can be just as important as what it encodes.
The investigators then discovered a novel function of desmoplakin, a protein best known for its role in desmosomes, the adhesive structures that help skin cells stick together and weather physical stress. The study showed that desmoplakin recruits both ribosomes and mRNAs to the cell border via distinct molecular pathways, indicating a coordinated process rather than simply a passive accumulation of cellular parts.
Desmoplakin’s unexpected partners in this process included components of the RNA-induced silencing complex (RISC), a molecular system that uses small RNAs, known as microRNAs, to repress gene expression.
“That was very striking,” he said. “We never thought that microRNA machinery would be associated with proteins at the cell membrane. We always assumed these components were functioning broadly in the cytosol.”
Next, the team studied what the cortex-localized mRNAs were actually doing. Despite sitting next to ribosomes, many of them were not being translated into proteins. Instead, they were actively repressed by microRNAs.
That changes dramatically after injury, according to the study. When the epithelial layer was damaged in scratch-wound experiments, the same mRNAs that had previously been silenced became active.
In effect, the cell has a stockpile of ready-to-use instructions positioned along its borders, which can be activated to produce proteins needed for repair, restructuring and restoring the tissue barrier.
“The cells are basically always ready to deal with stress,” Yi said. “They bring a bunch of mRNAs to the membrane, but under homeostatic conditions, they don’t make the proteins. Those messages are stored there.”
Understanding mRNA localization and translation could open new avenues for studying wound-healing disorders and diseases in which epithelial integrity breaks down. Desmosomes and microRNAs are both implicated in diseases ranging from skin blistering disorders to cancer, Yi said.
“This gives us a higher-dimensional way to think about what microRNAs are doing,” said Yi, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the director of Hair Alopecia Innovation and Research (HAIR) program of Northwestern Medicine. “It’s not just whether they repress a target, but where in the cell that regulation is happening.”
More broadly, the findings add to a growing appreciation that gene regulation is not just about DNA and RNA sequences and molecular signals, but also about cellular positioning. In this case, the edge of the cell serves as a control hub for cellular machinery, quietly maintaining the cell barrier and springing into action when that barrier is compromised.
“This means the cell’s zip code system is far more sophisticated than we thought,” Yi said.
Terry Lechler, PhD, professor in Dermatology at Duke University, was cooresponding author of the study.
The study was supported by National Institutes of Health grants R01-AR067203, R01-AR081081, R01-AR083352, R01-GM139480 and R01AR066703.
