Regulation of MYC by CARD14 in human epithelium is a determinant of epidermal homeostasis and disease
Stanley B. DeVore,
Matthew Schuetz,
Lauren Alvey,
Henry Lujan,
David E. Ochayon,
Lindsey Williams,
Wan Chi Chang,
Alyssa Filuta,
Brandy Ruff,
Arjun Kothari,
Jennifer M. Hahn,
Eric Brandt,
Latha Satish,
Krishna Roskin,
Andrew B. Herr,
Jocelyn M. Biagini,
Lisa J. Martin,
Deniz Cagdas,
Sevgi Keles,
Joshua D. Milner,
Dorothy M. Supp,
Gurjit K. Khurana Hershey
Affiliations
Stanley B. DeVore
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Matthew Schuetz
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Lauren Alvey
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Henry Lujan
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
David E. Ochayon
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Lindsey Williams
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Wan Chi Chang
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Alyssa Filuta
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Brandy Ruff
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Arjun Kothari
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Jennifer M. Hahn
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Eric Brandt
Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Latha Satish
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Krishna Roskin
Division of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Andrew B. Herr
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Jocelyn M. Biagini
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Lisa J. Martin
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Biostatistics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Deniz Cagdas
Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ihsan Dogramaci Children’s Hospital, Institutes of Child Health, Ankara 06230, Turkey
Sevgi Keles
Division of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya 42090, Turkey
Joshua D. Milner
Department of Pediatrics, Columbia University, New York, NY 10027, USA
Dorothy M. Supp
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Scientific Staff, Shriners Children’s Ohio, Dayton, OH 45404, USA
Gurjit K. Khurana Hershey
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Asthma Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Corresponding author
Summary: Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin.
