Rab11a Is Essential for Lamellar Body Biogenesis in the Human Epidermis

Abstract

Most of the skin barrier function is attributable to the outermost layer of the epidermis, the stratum corneum, which is composed of flattened, anucleated cells called corneocytes surrounded by a lipid-enriched lamellar matrix. The composition of the stratum corneum is directly dependent on the underlying granular keratinocytes, which are the last living cells in the stratified epidermis. Many components present in the intercorneocyte matrix are delivered by the underlying granular keratinocytes through a secretion process dependent on lysosome-related organelles called lamellar bodies. Because of the importance of lamellar bodies in the maintenance of the epidermal barrier, the mechanisms regulating their biogenesis must be better understood. In this study, we show that the Rab11a GTPase is highly expressed in terminally differentiated keratinocytes, where it is partly associated with lamellar bodies. Rab11a silencing in three-dimensional in vitro reconstructed human epidermis induces a barrier defect, a decrease in the amount of lipid found in the stratum corneum, a reduction in lamellar body density and secretion areas in granular keratinocytes, and the mis-sorting of lamellar body cargoes being driven to the lysosomal degradation pathway. Our results highlight the importance of Rab11a-dependent regulation of lamellar body biogenesis in keratinocytes and consequently on epidermal barrier homeostasis.

Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification

“…Although this interaction and the activity of Rab11a do not appear necessary for LH3 delivery to intracellular collagen (Banushi et al., 2016), Rab11a has recently been shown to be essential for skin homeostasis, specifically for epidermal lamellar body (LB) biogenesis (Reynier et al., 2016). LBs are lysosome-related organelles containing, amongst other cargoes, lipids and lipid-modifying enzymes that are secreted by granular layer keratinocytes and are fundamental for the development and maintenance of the epidermal barrier (Feingold, 2012, Feingold and Elias, 2014).…”

“…The underlying pathology of the skin phenotype in VPS33B deficiency has previously been attributed to defective LB secretion (Hershkovitz et al., 2008), and Rab11a has recently been shown to be essential for LB biogenesis (Reynier et al., 2016). We demonstrate here that the p.Gly131Glu variant disrupts the interaction of VPS33B-VIPAR with Rab11a and VPS33B deficiency causes abnormal formation of LB structures in mouse and human epidermis, suggesting that this interaction with Rab11a is important for LB biogenesis.…”

Lowering relative humidity level increases epidermal protein deimination and drives human filaggrin breakdown

“…RHEs, produced with keratinocytes from 3 different donors, were processed as previously described [32] and observed with an HT7700 electron microscope (Hitachi, Tokyo, Japan). Quantifications were performed using 2 RHEs/condition/donor.…”

Molecular basis of the skin barrier structures revealed by electron microscopy

“…The mammalian genome encodes three Rab11 proteins, Rab11a, b and c. Tissue expression of Rab11 proteins is variable; Rab11a is the one highly expressed in differentiated keratinocytes. It is associated with the CHEVI complex and is necessary for LG membrane trafficking (Figures and B) . The CHEVI complex interacts with soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor proteins (SNAREs), which mediate vesicle fusion with the target membrane.…”