Our skin – the body’s largest organ – provides the first line of defense against infection and many other threats to our health. Decades of research have shown that a wide range of diseases can occur or worsen when the skin cannot form an effective barrier.
Now, experts in human genetics and asthma research at Cincinnati Children’s report discovering a new molecular signaling pathway that plays a key role in maintaining our skin barrier. The extensive findings may eventually lead to new ways to prevent and treat inflammatory skin conditions such as atopic dermatitis (AD or eczema) and psoriasis.
The study was published online Aug. 6, 2024, at Cell references. The team of 22 co-authors was led by first author Stanley DeVore, PhD, and corresponding author Gurjit Khurana Hershey, MD, PhD.
Our research discovered a previously unknown cellular pathway involving the CARD14 protein. When this protein works properly, it keeps our skin barrier healthy, but when CARD14 doesn’t work properly, it promotes the development of skin diseases.
We found that CARD14 directly binds and regulates MYC, a protein involved in the control of cell growth that can contribute to cancer when it malfunctions. Our study shows that the correct interaction between these two proteins is important for a healthy skin barrier and protection against eczema and psoriasis. Furthermore, given MYC’s association with cancer, our findings also suggest that dysfunctional CARD14-MYC signaling may contribute to certain types of cancer throughout the body.”
Stanley DeVore, First Author
Barrier protection that goes deeper than the skin
Previous research has focused on the CARD14-NFκB signaling pathway, which is thought to promote psoriatic disease when elevated and to promote atopic dermatitis when decreased. Millions of people are affected by these and other inflammatory skin disorders.
“However, this model does not fully explain the variability in CARD14-driven diseases,” says Hershey, who directs the Division of Asthma Research at Cincinnati Children’s. “This novel CARD14-MYC signaling pathway reinforces the link between CARD14 and skin barrier health. Its signals regulate MYC function in the skin’s most common cell type.”
The study’s co-authors say that CARD14 regulates skin barrier function through two mechanisms: stimulation of NFκB to create an antimicrobial barrier and stimulation of MYC to create a physical barrier.
The study further explores how various mutations in CARD14 can promote various skin diseases, including AD and psoriasis. 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 new pathway may also contribute to some cancers that start in epithelial tissues.
Next steps
DeVore says the hunt is on to identify small-molecule agents that can safely affect the CARD14-MYC pathway. In fact, aspects of the study have been included in a recent patent filing.
“Our ultimate goal is to develop new treatments,” says DeVore. “We are also conducting studies aimed at identifying cancers that may be affected by CARD14-MYC signaling.”
In the meantime, the authors plan to share their findings at the 2025 Joint Conference of the American Academy of Allergy, Asthma and Immunology (AAAAI) and the World Allergy Organization (WAO), which will be held from February 28 to March 3 in San Diego .
About the study
Co-authors from Cincinnati Children’s include Matthew Schuetz, BS; Lauren Alvey, BS; Henry Lujan, PhD; David Ochayon, PhD; Lindsey Williams, BS; Wan-Chi (Daisy) Chang, MS; Alyssa Filuta, MS; Brandy Ruff, BS; Arjun Kothari, MEng; Eric Brandt, PhD; Latha Satish, PhD; Krishna Roskin, PhD; Andrew Herr, PhD; Jocelyn Biagini, PhD; and Lisa Martin, PhD.
Funding sources for this work include the National Institutes of Health (U19AI70235, T32GM063483, R01AI162964, and T32ES010957). The Cincinnati Children’s Flow Cytometry Research Service, the Bio-Imaging and Analysis Facility, the Integrative Pathology Research Unit, and the Genomics Sequencing Facility also contributed.
Source:
Journal Reference:
DeVore, SB, et al. (2024). MYC regulation by CARD14 in human epithelium is a determinant of epidermal homeostasis and disease. Cell references. doi.org/10.1016/j.celrep.2024.114589.
