KLF5 governs sphingolipid metabolism and barrier function of the skin

Abstract

Stem cells are fundamental units of tissue remodeling whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward-stratifying progenies, skin relies on its secretory functions to form the outermost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. KLF5 binds to and transcriptionally regulates genes encoding rate-limiting sphingolipid metabolism enzymes. Remarkably, skin barrier defects elicited by KLF5 ablation can be rescued by dietary interventions. Finally, we found that KLF5 is widely suppressed in human diseases with disrupted epidermal secretion, and its regulation of sphingolipid metabolism is conserved in human skin. Altogether, we established KLF5 as a disease-relevant transcription factor governing sphingolipid metabolism and barrier function in the skin, likely representing a long-sought secretory lineage-defining factor across tissue types.

Generating detailed intercellular communication patterns in psoriasis at the single-cell level using social networking, pattern recognition, and manifold learning methods to optimize treatment strategies

“…IRF3, a member of the IRF family, is implicated in the STING-IRF3 pathway, suggesting potential improvements in psoriasis treatment through its inhibition [ 48 ]. KLF5, a member of the Krupp-like factor subfamily, regulates sphingolipid metabolism and barrier function in the skin [ 49 ].…”

Genetic Variants Associated With Hidradenitis Suppurativa

“…At the chr13 locus, the closest protein-coding genes are the transcriptional regulators KLF12 and KLF5 , located approximately 260 kb and approximately 340 kb away, respectively. Deletion of KLF5 alters the skin barrier, and its expression is lower in human diseases with disrupted epidermal sphingolipid secretion . A variant at this locus, rs61957178, is located in a keratinocyte regulatory element (Figure 3) that may have a long-range effect on KLF5 and/or KLF12 .…”

“…Overexpression of mouse KLF5 , a critical regulator of sphingolipid-metabolizing and secreting enzymes in the skin, led to hyperkeratosis, follicular occlusion, and skin erosions, which are characteristic of HS . Deletions of KLF5 disrupt barrier function and have been associated with atopic dermatitis, nonhealing wounds, and IL-17–driven colitis in mice . Colitis induced by KLF5 deletion was associated with altered gut microbiota and stimulation of the IL-22/STAT3/IL-17 pathway.…”

“…Remarkably, genes at the 2 loci appear to have directly opposing and/or complementary roles in epithelial differentiation. The KLF5 gene is present primarily in epidermal keratinocytes that do not express SOX9 , which is primarily expressed in the hair bulge . The KLF5 gene functions as a regulator of epidermal stem cells, while SOX9 is a primary regulator of hair follicle stem cells.…”

The direct binding of bioactive peptide Andersonin-W1 to TLR4 expedites the healing of diabetic skin wounds

“…As the largest human organ, the skin not only is the first line of defense against attack and pathogen invasion but also plays an important role in physiological processes [ 1 , 2 ]. Skin structure integrity is crucial for its physiological functions [ 3 ].…”