Cincinnati Children’s Hospital Medical Center Study Looks at CARD14 & Healthy Skin Barrier Formation

Experts in human genetics and asthma research at Cincinnati Children’s Hospital Medical Center (Cincinnati Children’s) report discovering a novel molecular signaling pathway that plays a crucial role in maintaining the skin barrier. The findings could lead to new ways to prevent atopic dermatitis and psoriasis, say the scientists behind the research.

The study was published online in Cell Reports on Aug. 6, 2024. The title of the study is: “Regulation of MYC by CARD14 in human epithelium is a determinant of epidermal homeostasis and disease.”

The researchers discovered a previously unknown cellular pathway involving the protein CARD14, according to first author Stanley DeVore, PhD.

When the  protein works properly, it keeps the skin barrier healthy, but when CARD14 is not working properly, it promotes the development of skin disease, asserts DeVore.

“We found that CARD14 directly binds and regulates MYC, a protein involved in controlling cell growth that can contribute to cancer when it malfunctions. Our study shows that the proper interaction between these two proteins is important for a healthy skin barrier and protecting against eczema and psoriasis. Additionally, given the association of MYC with cancer, our findings also suggest that dysfunctional CARD14-MYC signaling may contribute to certain types of cancer throughout the body,” DeVore said.

Previous research has focused on the CARD14-NFκB signaling pathway, which is thought to promote psoriatic diseases when elevated and to promote atopic dermatitis when reduced.

“However, that model does not fully explain the variability in CARD14-driven diseases,” noted corresponding author Gurjit Khurana Hershey, MD, PhD, who directs the Division of Asthma Research at Cincinnati Children’s.

“This new CARD14-MYC signaling pathway strengthens the link between CARD14 and skin barrier health. Its signals regulate the function of MYC in the most common type of skin cell,” noted Dr. Hershey.

The study team spanned 22 co-authors.

The authors contend CARD14 regulates skin barrier function through two mechanisms: stimulating NFκB to establish an antimicrobial barrier and stimulating MYC to help build a physical barrier.

The study further explored how various mutations in CARD14 can promote different skin diseases. Importantly, the study reports that altered CARD14-MYC signaling could affect barrier function and allergic diseases in other tissues, contributing to asthma by affecting airway tissue linings or contributing to eosinophilic esophagitis by affecting the digestive tract.  The novel pathway may also contribute to certain cancers that begin in epithelial tissues, asserted the study authors.

What’s Next

DeVore says “the hunt is on” to identify small-molecule agents that can safely influence the CARD14-MYC pathway. Aspects of the study have been included in a recent patent filing.

“Our ultimate goal is to develop novel therapeutics,” DeVore says. “We also are conducting studies aimed at identifying cancers that may be affected by CARD14-MYC signaling.”

The co-authors plan to share their findings at the 2025 Joint Conference of the American Academy of Allergy, Asthma and Immunology and the World Allergy Organization in 2025.

Funding sources for this work include the National Institutes of Health (U19AI70235, T32GM063483, R01AI162964, and T32ES010957). The Cincinnati Children’s Research Flow Cytometry Facility, Bio-Imaging and Analysis Facility, Integrated Pathology Research Facility, and Genomics Sequencing Facility also contributed.