Antimicrobial Late Cornified Envelope Proteins: The Psoriasis Risk Factor Deletion of LCE3B/C Genes Affects Microbiota Composition

Hanna Niehues,Patrick A.M. Jansen,Jos P.H. Smits,Rob Mesman,Thomas H.A. Ederveen,Ellen H. van den Bogaard,Joost Schalkwijk,Danique A. van der Krieken,Mihai G. Netea,Laura van Niftrik,Patrick L.J.M. Zeeuwen

doi:10.1016/j.jid.2021.11.036

Hanna Niehues, Patrick A.M. Jansen + Show 9 more

Open Access

https://doi.org/10.1016/j.jid.2021.11.036

Copy DOI

Abstract

Late cornified envelope proteins are predominantly expressed in the skin and other cornified epithelia. On the basis of sequence similarity, this 18-member homologous gene family has been subdivided into six groups. The LCE3 proteins have been the focus of dermatological research because the combined deletion of LCE3B and LCE3C genes (LCE3B/C-del) is a risk factor for psoriasis. We previously reported that LCE3B/C-del increases the expression of the LCE3A gene and that LCE3 proteins exert antibacterial activity. In this study, we analyzed the antimicrobial properties of other family members and the role of LCE3B/C-del in the modulation of microbiota composition of the skin and oral cavity. Differences in killing efficiency and specificity between the late cornified envelope proteins and their target microbes were found, and the amino acid content rather than the order of the well-conserved central domain of the LCE3A protein was found responsible for its antibacterial activity. Invivo, LCE3B/C-del correlated with a higher beta-diversity in the skin and oral microbiota. From these results, we conclude that all late cornified envelope proteins possess antimicrobial activity. Tissue-specific and genotype-dependent antimicrobial protein profiles impact skin and oral microbiota composition, which could direct toward LCE3B/C-del‒associated dysbiosis and a possible role for microbiota in the pathophysiology of psoriasis.

Highlights

The skin protects against dehydration and infection owing to the barrier function of the epidermis
The most broad-spectrum antibacterial activity was demonstrated for LCE6A, being active against all strains tested, whereas LCE1F only showed the complete killing of Corynebacterium aurimucosum
Since the discovery of the late cornified envelope (LCE) gene family (Marshall et al, 2001), it took almost 10 years before the LCE3B/C-del was identified as a risk factor for developing psoriasis, and another decade later, we provided

Summary

Introduction

The skin protects against dehydration and infection owing to the barrier function of the epidermis. In the last living epidermal cell layer, the stratum granulosum, structural proteins such as FLG, hornerin, and the family of late cornified envelope (LCE) proteins are expressed These were thought to be exclusively contributing to the formation of corneocytes and the physical barrier of the skin. Hornerin and LCEs are classified as cationic intrinsically disordered antimicrobial peptides (AMPs), in which high content of disorder-promoting amino acids define the antimicrobial effect of these proteins (Latendorf et al, 2019). These latest findings highlight the function and importance of previously thought to be exclusive structural epidermal proteins in skin barrier homeostasis

Objectives

Methods

Results

Conclusion