CYSRT1: An Antimicrobial Epidermal Protein that Can Interact with Late Cornified Envelope Proteins

• Published in: Journal of investigative dermatology Vol. 143; no. 8; pp. 1498 - 1508.e7
• Main Authors: Niehues, Hanna, Rikken, Gijs, Kersten, Ferry F.J., Eeftens, Jorine M., van Vlijmen-Willems, Ivonne M.J.J., Rodijk-Olthuis, Diana, Jansen, Patrick A.M., Hendriks, Wiljan J.A.J., Ederveen, Thomas H.A., Schalkwijk, Joost, van den Bogaard, Ellen H., Zeeuwen, Patrick L.J.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2023
• Subjects: Anti-Infective Agents - metabolism; Cornified Envelope Proline-Rich Proteins - genetics; Cornified Envelope Proline-Rich Proteins - metabolism; Epidermis - metabolism; Humans; Keratinocytes - metabolism; Proteins - metabolism; Psoriasis - genetics; Psoriasis - metabolism; Skin - metabolism; AMP; KC; HEE; AHR; Co-IP; Y2H; CIDAMP; LCE
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2023.01.022

Late cornified envelope (LCE) proteins are small cationic epidermal proteins with antimicrobial properties, and the combined deletion of LCE3B and LCE3C genes is a risk factor for psoriasis that affects skin microbiome composition. In a yeast two-hybrid screen, we identified CYSRT1 as an interacting partner of members of all LCE groups except LCE6. These interactions were confirmed in a mammalian cell system by coimmunoprecipitation. CYSRT1 is a protein of unknown function that is specifically expressed in cutaneous and oral epithelia and spatially colocalizes with LCE proteins in the upper layers of the suprabasal epidermis. Constitutive CYSRT1 expression is present in fully differentiated epidermis and can be further induced in vivo by disruption of the skin barrier upon stratum corneum removal. Transcriptional regulation correlates to keratinocyte terminal differentiation but not to skin bacteria exposure. Similar to LCEs, CYSRT1 was found to have antibacterial activity against Pseudomonas aeruginosa. Comparative gene sequence analysis and protein amino acid alignment indicate that CYSRT1 is highly conserved among vertebrates and has putative antimicrobial activity. To summarize, we identified CYSRT1 in the outer skin layer, where it colocalizes with LCE proteins and contributes to the constitutive epidermal antimicrobial host defense repertoire.