Niehues Hanna, Tsoi Lam C, van der Krieken Danique A, Jansen Patrick A M, Oortveld Merel A W, Rodijk-Olthuis Diana, van Vlijmen Ivonne M J J, Hendriks Wiljan J A J, Helder Richard W, Bouwstra Joke A, van den Bogaard Ellen H, Stuart Philip E, Nair Rajan P, Elder James T, Zeeuwen Patrick L J M, Schalkwijk Joost
Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
J Invest Dermatol. 2017 Nov;137(11):2380-2388. doi: 10.1016/j.jid.2017.06.003. Epub 2017 Jun 17.
Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. 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 epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3-dimensional skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of bacterial taxa at low micromolar concentrations. No genotype-dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del-mediated psoriasis risk.
终末分化的表皮角质形成细胞表达大量结构蛋白和抗菌蛋白，这些蛋白参与角质层的物理屏障功能，并提供先天性皮肤宿主防御。晚期角质化包膜（LCE）基因位于1号染色体上的表皮分化复合体中，编码一个由18种功能未知的蛋白质组成的家族，其表达主要局限于表皮。LCE3B和LCE3C这两个成员的缺失（LCE3B/C缺失）是一个广泛复制的银屑病风险因素，它与主要的银屑病风险基因HLA-C*06相互作用。在这里，我们利用来自人类皮肤的RNA测序数据进行了数量性状基因座分析，发现LCE3B/C缺失与LCE3A的表达显著增加有关，LCE3A是一个与LCE3B/C缺失直接相邻的基因。我们使用来自LCE3B/C缺失基因分型供体的原代角质形成细胞在三维皮肤模型中证实了这些发现。功能分析表明，LCE3蛋白，特别是LCE3A，在低微摩尔浓度下对多种细菌类群具有防御素样抗菌活性。对于由内而外或由外而内的物理皮肤屏障功能，未观察到基因型依赖性效应。我们的研究结果确定了LCE3蛋白的一种未知生物学功能，并提示其在表皮宿主防御和LCE3B/C缺失介导的银屑病风险中发挥作用。
