694 Psoriasis-associated late cornified envelope (LCE) proteins have antibacterial activity

Abstract

Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to the epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely replicated psoriasis risk factor that interacts with the major psoriasis-risk gene HLA-C*06. Disease associated genetic risk factors often involve non-coding variants, which has precluded understanding of their functional consequences in complex diseases. We aimed to investigate the expression and function of the LCE proteins to explain the biology that underlies the association between LCE3B/C-del and psoriasis. We used cis-expression quantitative trait locus (eQTL) analysis and functional assays of LCE proteins in in vivo skin and 3D epidermal models. RNA-seq data from normal and psoriatic human skin revealed that LCE3B/C-del was associated with a significant induction of the LCE3A, directly adjacent to the LCE3B/C-del. This phenomenon was most strongly present in normal skin, where the LCE3A gene is silent when LCE3B and LCE3C are present. We confirmed these findings in a 3D epidermal equivalent model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis did not support a role for LCE proteins in epidermal barrier function, but revealed that psoriasis-associated LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a broad variety of bacterial taxa at low micromolar concentrations. Our findings identify a hitherto unknown biological function for LCE3 proteins and suggest a central role for LCE3A in epidermal host defense and LCE3B/C-del mediated psoriasis risk.