Proteins That Strengthen Skin Also Control Cell Signaling, Study Finds

A large family of proteins that gives human skin its mechanical strength also appears to organize the molecular signals that control skin cell activity, according to a study led by researchers at UT Southwestern Medical Center. The team’s findings, published in Developing cellcould lead to new ways to fight a host of skin diseases, including ulcers and skin cancer.

“We never really know why skin needs so many proteins and their complex expression patterns to provide mechanical strength. Researchers have been very interested in what else these proteins might do, and we are finally starting to get some answers,” said first author Benjamin Nanes, MD, PhD, assistant professor of dermatology and member of the Lyda Hill Department of Bioinformatics at UT Southwestern.

Dr. Nanes led the study under the mentorship of Gaudenz Danuser, Ph.D., chair and professor of bioinformatics and professor of cell biology, who was the study’s senior author.

Dr. Nanes explains that skin gets its mechanical strength from keratin intermediate filaments (KIFs), rope-like proteins that crisscross the insides of skin cells and form connections between them. This protein family includes 54 members, which cells produce in different combinations depending on the circumstances.

For example, when skin is injured, it increases the abundance of KIFs known as K6A, K6B, K6C, K16, and K17 to a greater extent than other KIFs. However, because skin resistance remains roughly the same despite different circumstances, the need for so many different members of the KIF family and how changes in their relative abundance affect processes like wound healing are unclear.

Scientists often study the role of specific proteins by mutating or deleting the gene responsible for their production. However, according to Dr. Nanes, studying KIFs using this strategy would only weaken the skin, making it impossible to separate their role in providing mechanical strength from the other possible functions they perform.

To avoid this drawback, he and his colleagues genetically engineered two batches of skin cells: one that produced more of the wound-associated KIF K6A and the other that produced more of the KIF associated with intact skin, known as K5. After allowing these cells to grow into skin organoids that formed layers typical of natural skin, the researchers compared how the cells in each organoid behaved.

They found that cells with higher K6A migrated more easily than cells with higher K5, allowing them to better close wounds generated in skin organoids. However, cell migration depends on different proteins called myosin motors that generate the forces needed for traction. The function of myosin motors is not directly linked to KIFs.

As they continued their research, the researchers showed that the relative abundance of K6A altered the functioning of a molecular switch that activates myosin: More K6A triggered more myosin to activate, which caused cells to move. Less K6A prevented these motors from starting.

Although it is not entirely clear why K6A is able to activate myosin more efficiently, Dr. Danuser speculated that different KIFs might serve as places where molecules involved in cellular control can come together and form the complexes needed to turn certain activities on or off.

“By acting as platforms on which different signaling molecules come together, KIFs could increase the chances that these molecules will meet to trigger various functions in cells,” he said.

Dr. Nanes plans to test this hypothesis in future studies and to investigate other molecular switches that might rely on KIFs.