Two proteins with opposing functions orchestrate the development and maintenance of healthy skin, Stanford Medicine researchers found, according to a June 25 study. The research suggests that modulating these proteins' activity with topical drugs could reduce inflammation, aid wound healing, and slow or halt the growth of skin cancer.
The proteins belong to a family called ubiquitin-like proteins. While ubiquitination typically controls the destruction of unneeded cellular proteins, certain ubiquitin-like proteins in the skin instead switch on or off wide swaths of genes involved in cellular growth and development. This process triggers progenitor stem cells in the lower layer of the skin to either mature and migrate to the surface or self-renew.
"These two ubiquitin-like protein systems are remarkably dedicated and opposite in their functions," said Paul Khavari, MD, PhD, chair of dermatology at Stanford School of Medicine and senior author. "One promotes the stem-cell state while the other drives differentiation. It's like having two opposing forces that determine a cell's fate." Clinical instructor Mårten Winge added, "What's really exciting is how specific these effects are. When we manipulate one system or the other, we see very clear and opposite outcomes. This specificity is unusual for ubiquitin-like pathways and makes these systems particularly attractive for therapeutic targeting."
Researchers used various experimental approaches to assess changes in gene expression during keratinocyte differentiation—the process by which progenitor cells become specialized barrier-forming cells at the skin surface. Disrupting more than 200 genes within this pathway highlighted two subpathways essential for proper differentiation: NEDDylation and SUMOylation. Blocking NEDDylation accelerated differentiation; blocking SUMOylation prevented it.
Further tests using genetically engineered mice showed that halting expression of key pathway proteins led to abnormal skin development—overgrowth resembling psoriasis when Nedd8 was absent, impaired differentiation when Sumo2 was lacking—and altered immune cell populations within affected tissue.
Khavari said, "We're not just changing individual cells - we're changing the whole tissue microenvironment... Manipulating these pathways could have therapeutic applications for wounds, inflammation, skin aging and even cancer." The team is now exploring whether topical drug treatments targeting these pathways could treat various skin diseases.
