Rab25 Deficiency Perturbs Epidermal Differentiation and Skin Barrier Function in Mice

Abstract

Rab25, a member of the Rab11 small GTPase family, is central to achieving cellular polarity in epithelial tissues. Rab25 is highly expressed in epithelial cells of various tissues including breast, vagina, cervix, the gastrointestinal tract, and skin. Rab25 plays key roles in tumorigenesis, mainly by regulating epithelial differentiation and proliferation. However, its role in skin physiology is relatively unknown. In this study, we demonstrated that Rab25 knock-out (KO) mice show a skin barrier dysfunction with high trans-epidermal water loss and low cutaneous hydration. To examine this observation, we investigated the histology and epidermal differentiation markers of the skin in Rab25 KO mice. Rab25 KO increased cell proliferation at the basal layer of epidermis, whereas the supra-basal layer remained unaffected. Ceramide, which is a critical lipid component for skin barrier function, was not altered by Rab25 KO in its distribution or amount, as determined by immunohistochemistry. Notably, levels of epidermal differentiation markers, including loricrin, involucrin, and keratins (5, 14, 1, and 10) increased prominently in Rab25 KO mice. In line with this, depletion of Rab25 with single hairpin RNA increased the expression of differentiation markers in a human keratinocyte cell line, HaCaT. Transcriptomic analysis of the skin revealed increased expression of genes associated with skin development, epidermal development, and keratinocyte differentiation in Rab25 KO mice. Collectively, these results suggested that Rab25 is involved in the regulation of epidermal differentiation and proliferation.

Lack of IRF6 Disrupts Human Epithelial Homeostasis by Altering Colony Morphology, Migration Pattern, and Differentiation Potential of Keratinocytes

“…Another study confirmed that Irf6 knockout murine keratinocytes did not affect the regulation of the components of desmosomes ( Ferone et al, 2013 ). Two proteins, RAB25 and SULT2B2, which are known to be associated with healthy skin and the regulation of epidermal differentiation and proliferation, have also been found to be robustly decreased in the absence of IRF6 in skin-derived keratinocytes ( Heinz et al, 2017 ; Jeong et al, 2019 ).…”

RAB25 coordinates filaggrin‐containing keratohyalin granule maturation and affects atopic dermatitis severity

“…To investigate mechanism of RAB25-dependent FLG maturation, we used transcriptome data obtained from our previous study. 26 Transcriptomics analysis of the epidermis from skin samples of WT and Rab25 KO mice revealed that cytoskeleton-related gene sets were altered by Rab25 KO, which were among the top 10 gene ontology terms (Figure 5A). Consistently, gene set enrichment analysis (GSEA) showed that gene sets related with actin binding and regulation of the actin cytoskeleton were negatively enriched in Rab25 KO mice compared with that in WT mice (Figure 5B).…”

“…Recently, we demonstrated that RAB25 deficiency impairs the trafficking of integrins in keratinocytes 25 . Moreover, Rab25 knockout (KO) in mice caused skin barrier dysfunction and disrupted epidermal differentiation 26 . Although previous studies revealed that RAB11 contributed to skin barrier function via regulation of lamellar granule in granular keratinocyte, 27,28 the underlying mechanism of RAB25 in skin physiology has yet to be clarified.…”

Data-independent acquisition mass spectrometry quantitative proteomic analysis reveals that skin aging-related proteins differ between men and women

“…Deletion of Rab25 can impair the transport of integrin, so Rab25 plays an important role in regulating the differentiation and proliferation of keratinocytes. A lack of Rab25 will disrupt epidermal differentiation and skin barrier function, leading to increased transdermal water loss and reduced skin moisture (Jeong et al, 2019). Therefore, RAB25 is essential for maintaining skin barrier function.…”